2,3,5-trisubstituted thiophene compounds and uses thereof

ABSTRACT

The present invention provides a compound of formula I: 
                         
a method for manufacturing the compounds of the invention, and its therapeutic uses. The present invention further provides a combination of pharmacologically active agents and a pharmaceutical composition.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. Ser. No. 13/810,277, filed Jan.15, 2013, which is the U.S. National Stage of International ApplicationNo. PCT/EP2011/062545, filed Jul. 21, 2011, which claims the benefit ofpriority to U.S. Provisional Application Ser. No. 61/366,687, filed onJul. 22, 2010, and U.S. Provisional Application Ser. No. 61/423,346,filed on Dec. 15, 2010.

FIELD OF THE INVENTION

Compounds and compositions, methods for their preparation, and methodsfor their use in treating viral infections in patients mediated, atleast in part, by a virus in the Flaviviridae family of viruses aredisclosed.

STATE OF THE ART

Chronic infection with HCV is a major health problem associated withliver cirrhosis, hepatocellular carcinoma, and liver failure. Anestimated 170 million chronic carriers worldwide are at risk ofdeveloping liver disease (Szabo, E. et al., Pathol.Oncol.Res. 2003,9:215-221; Hoofnagle J. H., Hepatology 1997, 26:15S-20S). In the UnitedStates alone 2.7 million are chronically infected with HCV, and thenumber of HCV-related deaths in 2000 was estimated between 8,000 and10,000, a number that is expected to increase significantly over thenext years. Infection by HCV is insidious in a high proportion ofchronically infected (and infectious) carriers who may not experienceclinical symptoms for many years. Liver cirrhosis can ultimately lead toliver failure. Liver failure resulting from chronic HCV infection is nowrecognized as a leading cause of liver transplantation.

HCV is a member of the Flaviviridae family of RNA viruses that affectanimals and humans. The genome is a single ˜9.6-kilobase strand of RNA,and consists of one open reading frame that encodes for a polyprotein of˜3000 amino acids flanked by untranslated regions at both 5′ and 3′ ends(5′- and 3′-UTR). The polyprotein serves as the precursor to at least 10separate viral proteins critical for replication and assembly of progenyviral particles. The organization of structural and non-structuralproteins in the HCV polyprotein is as follows:C-E1-E2-p7-NS2-NS3-NS4a-NS4b-NS5a-NS5b. Because the replicative cycle ofHCV does not involve any DNA intermediate and the virus is notintegrated into the host genome, HCV infection can theoretically becured.

At present, the standard treatment for chronic HCV is pegylatedinterferon alpha (IFN-alpha) in combination with ribavirin and thisrequires at least six (6) months of treatment. IFN-alpha belongs to afamily of naturally occurring small proteins with characteristicbiological effects such as antiviral, immunoregulatory, and antitumoralactivities that are produced and secreted by most animal nucleated cellsin response to several diseases, in particular viral infections.IFN-alpha is an important regulator of growth and differentiationaffecting cellular communication and immunological control. Treatment ofHCV with interferon has frequently been associated with adverse sideeffects such as fatigue, fever, chills, headache, myalgias, arthralgias,mild alopecia, psychiatric effects and associated disorders, autoimmunephenomena and associated disorders and thyroid dysfunction. Ribavirin,an inhibitor of inosine 5′-monophosphate dehydrogenase (IMPDH), enhancesthe efficacy of IFN-alpha in the treatment of HCV. Despite theintroduction of ribavirin, more than 50% of the patients do noteliminate the virus with the current standard therapy ofinterferon-alpha (IFN) and ribavirin. By now, standard therapy ofchronic hepatitis C has been changed to the combination of pegylatedIFN-alpha plus ribavirin. However, a number of patients still havesignificant side effects, primarily related to ribavirin. Ribavirincauses significant hemolysis in 10-20% of patients treated at currentlyrecommended doses, and the drug is both teratogenic and embryotoxic.Even with recent improvements, a substantial fraction of patients do notrespond with a sustained reduction in viral load and there is a clearneed for more effective antiviral therapy of HCV infection (Fried, M.W., et al. N. Engl. J Med 2002, 347:975-982).

A number of approaches are being pursued to combat the virus. Theseinclude, for example, application of antisense oligonucleotides orribozymes for inhibiting HCV replication. Furthermore, low-molecularweight compounds that directly inhibit HCV proteins and interfere withviral replication are considered as attractive strategies to control HCVinfection. Among the viral targets, the NS3/4a protease and the NS5bRNA-dependent RNA polymerase are considered the most promising viraltargets for new drugs (see Ni, Z. J. and Wagman, A. S. Curr. Opin. DrugDiscov. Devel. 2004, 7, 446-459; Beaulieu, P. L. and Tsantrizos, Y. S.Curr. Opin. Investig. Drugs 2004, 5, 838-850; and Griffith, R. C. etal., Ann. Rep. Med. Chem 39, 223-237, 2004). However, none of thesecompounds have progressed beyond clinical trials.

In view of the worldwide epidemic level of HCV and other members of theFlaviviridae family of viruses, and further in view of the limitedtreatment options, there is a strong need for new effective drugs fortreating infections cause by these viruses.

SUMMARY OF THE INVENTION

In a first embodiment, the invention provides compounds of Formula (I),compositions thereof and methods of using same to treat viral infection.In particular, the compounds of the invention as defined by Formula (I)are useful for the treatment or prevention of hepatitis C virusinfection and diseases associated with or caused by HCV infection. Thestructure of compounds of Formula (I) is as follows:

Compounds of Formula (I) includes salts thereof. Definitions forvariables present in Formula (I) are defined infra.

Unless specified otherwise, the term “compounds of the presentinvention” refers to compounds of Formula (I) and subformulae thereof(add other additional genus structures as necessary), prodrugs thereof,salts of the compound and/or prodrugs, hydrates or solvates of thecompounds, salts and/or prodrugs, as well as all stereoisomers(including diastereoisomers and enantiomers), tautomers and isotopicallylabeled compounds (including deuterium substitutions), as well asinherently formed moieties (e.g., polymorphs, solvates and/or hydrates).

In one embodiment provided is a pharmaceutical composition comprising apharmaceutically acceptable carrier and a therapeutically effectiveamount of a compound of Formula (I).

In other embodiments provided are methods for preparing the compounds ofFormula (I) and compositions thereof and for their therapeutic uses. Inone embodiment provided is a method for treating a viral infection in apatient mediated at least in part by a virus in the Flaviviridae familyof viruses, comprising administering to said patient a compositioncomprising a compound or a salt of Formula (I). In some aspects, theviral infection is mediated by hepatitis C virus.

These and other embodiments of the invention are further described inthe text that follows.

DETAILED DESCRIPTION OF THE INVENTION

Throughout this application, references are made to various embodimentsrelating to compounds, compositions, and methods. The variousembodiments described are meant to provide a variety of illustrativeexamples and should not be construed as descriptions of alternativespecies. Rather it should be noted that the descriptions of variousembodiments provided herein may be of overlapping scope. The embodimentsdiscussed herein are merely illustrative and are not meant to limit thescope of the present invention.

For purposes of interpreting this specification, the followingdefinitions will apply and whenever appropriate, terms used in thesingular will also include the plural and vice versa.

As used herein, the term “alkyl” refers to a fully saturated branched orunbranched hydrocarbon moiety having up to 20 carbon atoms. Unlessotherwise provided, alkyl refers to hydrocarbon moieties having 1 to 16carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms, or 1 to 4carbon atoms. Representative examples of alkyl include, but are notlimited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl,iso-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl,3-methylhexyl, 2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl,n-octyl, n-nonyl, n-decyl and the like.

As used herein, the term “alkylene” refers to divalent alkyl group asdefined herein above having 1 to 20 carbon atoms. It comprises 1 to 20carbon atoms, Unless otherwise provided, alkylene refers to moietieshaving 1 to 16 carbon atoms, 1 to 10 carbon atoms, 1 to 7 carbon atoms,or 1 to 4 carbon atoms. Representative examples of alkylene include, butare not limited to, methylene, ethylene, n-propylene, iso-propylene,n-butylene, sec-butylene, iso-butylene, tert-butylene, n-pentylene,isopentylene, neopentylene, n-hexylene, 3-methylhexylene,2,2-dimethylpentylene, 2,3-dimethylpentylene, n-heptylene, n-octylene,n-nonylene, n-decylene and the like.

As used herein, the term “haloalkyl” refers to an alkyl as definedherein, that is substituted by one or more halo groups as definedherein. The haloalkyl can be monohaloalkyl, dihaloalkyl or polyhaloalkylincluding perhaloalkyl. A monohaloalkyl can have one iodo, bromo, chloroor fluoro within the alkyl group. Dihaloalky and polyhaloalkyl groupscan have two or more of the same halo atoms or a combination ofdifferent halo groups within the alkyl. Typically the polyhaloalkylcontains up to 12, or 10, or 8, or 6, or 4, or 3, or 2 halo groups.Non-limiting examples of haloalkyl include fluoromethyl, difluoromethyl,trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl,pentafluoroethyl, heptafluoropropyl, difluorochloromethyl,dichlorofluoromethyl, difluoroethyl, difluoropropyl, dichloroethyl anddichloropropyl. A perhaloalkyl refers to an alkyl having all hydrogenatoms replaced with halo atoms.

The term “aryl” refers to an aromatic hydrocarbon group having 6-20carbon atoms in the ring portion. Typically, aryl is monocyclic,bicyclic or tricyclic aryl having 6-20 carbon atoms.

Furthermore, the term “aryl” as used herein, refers to an aromaticsubstituent which can be a single aromatic ring, or multiple aromaticrings that are fused together.

Non-limiting examples include phenyl, naphthyl or tetrahydronaphthyl,each of which may optionally be substituted by 1-4 substituents, such asalkyl, trifluoromethyl, cycloalkyl, halogen, hydroxy, alkoxy, acyl,alkyl-C(O)—O—, aryl-O—, heteroaryl-O—, amino, thiol, alkyl-S—, aryl-S—,nitro, cyano, carboxy, alkyl-O—C(O)—, carbamoyl, alkyl-S(O)—, sulfonyl,sulfonamido, phenyl, and heterocyclyl.

As used herein, the term “alkoxy” refers to alkyl-O—, wherein alkyl isdefined herein above. Representative examples of alkoxy include, but arenot limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy,tert-butoxy, pentyloxy, hexyloxy, cyclopropyloxy-, cyclohexyloxy- andthe like. Typically, alkoxy groups have about 1-7, more preferably about1-4 carbons.

As used herein, the term “heterocyclyl” or “heterocyclo” refers to asaturated or unsaturated non-aromatic ring or ring system, e.g., whichis a 4-, 5-, 6-, or 7-membered monocyclic, 6-, 7-, 8-, 9-, 10-, 11-, or12-membered bicyclic or 10-, 11-, 12-, 13-, 14- or 15-membered tricyclicring system and contains at least one heteroatom selected from O, S andN, where the N and S can also optionally be oxidized to variousoxidation states. The heterocyclic group can be attached at a heteroatomor a carbon atom. The heterocyclyl can include fused or bridged rings aswell as spirocyclic rings. Examples of heterocycles includetetrahydrofuran (THF), dihydrofuran, 1,4-dioxane, morpholine,1,4-dithiane, piperazine, piperidine, 1,3-dioxolane, imidazolidine,imidazoline, pyrroline, pyrrolidine, tetrahydropyran, dihydropyran,oxathiolane, dithiolane, 1,3-dioxane, 1,3-dithiane, oxathiane, andthiomorpholine.

The term “heterocyclyl” further refers to heterocyclic groups as definedherein substituted with 1 to 5 substituents independently selected fromthe groups consisting of the following:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., ═O;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic groupbonded through an oxygen bridge;

(j) alkyl-O—C(O)—;

(k) mercapto;

(l) amido or carboxamido

(m) cyano;

(n) sulfamoyl, sulfamido or sulfonamido;

(o) aryl;

(p) alkyl-C(O)—O—;

(q) aryl-C(O)—O—;

(r) aryl-S—;

(s) aryloxy;

(t) alkyl-S—;

(u) formyl, i.e., HC(O)—;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

(y) alkyl substituted with cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “cycloalkyl” refers to saturated or unsaturatedmonocyclic, bicyclic or tricyclic hydrocarbon groups of 3-12 carbonatoms. Unless otherwise provided, cycloalkyl refers to cyclichydrocarbon groups having between 3 and 9 ring carbon atoms or between 3and 7 ring carbon atoms, each of which can be optionally substituted byone, or two, or three, or more substituents independently selected fromthe group consisting of alkyl, halo, oxo, hydroxy, alkoxy, alkyl-C(O)—,acylamino, carbamoyl, alkyl-NH—, (alkyl)₂N—, thiol, alkyl-S—, nitro,cyano, carboxy, alkyl-O—C(O)—, sulfonyl, sulfonamido, sulfamoyl,sulfamido, and heterocyclyl. Exemplary monocyclic hydrocarbon groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclopentenyl, cyclohexyl and cyclohexenyl and the like. Exemplarybicyclic hydrocarbon groups include bornyl, indyl, hexahydroindyl,tetrahydronaphthyl, decahydronaphthyl, bicyclo[2.1.1]hexyl,bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl,6,6-dimethylbicyclo[3.1.1]heptyl, 2,6,6-trimethylbicyclo[3.1.1]heptyl,bicyclo[2.2.2]octyl and the like. Exemplary tricyclic hydrocarbon groupsinclude adamantyl and the like.

As used herein, the term “aryloxy” refers to both an —O-aryl and an—O-heteroaryl group, wherein aryl and heteroaryl are defined herein.

As used herein, the term “heteroaryl” refers to a 5-14 memberedmonocyclic- or bicyclic- or tricyclic-aromatic ring system, having 1 to8 heteroatoms selected from N, O or S. Typically, the heteroaryl is a5-10 membered ring system (e.g., 5-7 membered monocycle or an 8-10memberred bicycle) or a 5-7 membered ring system. Typical heteroarylgroups include 2- or 3-thienyl, 2- or 3-furyl, 2- or 3-pyrrolyl, 2-, 4-,or 5-imidazolyl, 3-, 4-, or 5-pyrazolyl, 2-, 4-, or 5-thiazolyl, 3-, 4-,or 5-isothiazolyl, 2-, 4-, or 5-oxazolyl, 3-, 4-, or 5-isoxazolyl, 3- or5-1,2,4-triazolyl, 4- or 5-1,2,3-triazolyl, tetrazolyl, 2-, 3-, or4-pyridyl, 3- or 4-pyridazinyl, 3-, 4-, or 5-pyrazinyl, 2-pyrazinyl, and2-, 4-, or 5-pyrimidinyl.

The term “heteroaryl” also refers to a group in which a heteroaromaticring is fused to one or more aryl, cycloaliphatic, or heterocyclylrings, where the radical or point of attachment is on the heteroaromaticring. Nonlimiting examples include 1-, 2-, 3-, 5-, 6-, 7-, or8-indolizinyl, 1-, 3-, 4-, 5-, 6-, or 7-isoindolyl, 2-, 3-, 4-, 5-, 6-,or 7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-indazolyl, 2-, 4-, 5-, 6-, 7-, or8-purinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, or 9-quinolizinyl, 2-, 3-, 4-,5-, 6-, 7-, or 8- quinoliyl, 1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinoliyl,1-, 4-, 5-, 6-, 7-, or 8-phthalazinyl, 2-, 3-, 4-, 5-, or6-naphthyridinyl, 2-, 3-, 5-, 6-, 7-, or 8-quinazolinyl, 3-, 4-, 5-, 6-,7-, or 8-cinnolinyl, 2-, 4-, 6-, or 7-pteridinyl, 1-, 2-, 3-, 4-, 5-,6-, 7-, or 8-4aH carbazolyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-, or8-carbzaolyl, 1-, 3-, 4-, 5-, 6-, 7-, 8-, or 9-carbolinyl, 1-, 2-, 3-,4-, 6-, 7-, 8-, 9-, or 10-phenanthridinyl, 1-, 2-, 3-, 4-, 5-, 6-, 7-,8-, or 9-acridinyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-perimidinyl, 2-,3-, 4-, 5-, 6-, 8-, 9-, or 10-phenathrolinyl, 1-, 2-, 3-, 4-, 6-, 7-,8-, or 9-phenazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or10-phenothiazinyl, 1-, 2-, 3-, 4-, 6-, 7-, 8-, 9-, or 10-phenoxazinyl,2-, 3-, 4-, 5-, 6-, or 1-, 3-, 4-, 5-, 6-, 7-, 8-, 9-, or10-benzisoqinolinyl, 2-, 3-, 4-, or thieno[2,3-b]furanyl, 2-, 3-, 5-,6-, 7-, 8-, 9-, 10-, or 11-7H-pyrazino[2,3-c]carbazolyl, 2-, 3-, 5-, 6-,or 7-2H-furo[3,2-b]-pyranyl, 2-, 3-, 4-, 5-, 7-, or8-5H-pyrido[2,3-d]-o-oxazinyl, 1-, 3-, or 5-1H-pyrazolo[4,3-d]-oxazolyl,2-, 4-, or 54H-imidazo[4,5-d]thiazolyl, 3-, 5-, or8-pyrazino[2,3-d]pyridazinyl, 2-, 3-, 5-, or 6-imidazo[2,1-b]thiazolyl,1-, 3-, 6-, 7-, 8-, or 9-furo[3,4-c]cinnolinyl, 1-, 2-, 3-, 4-, 5-, 6-,8-, 9-, 10, or 11-4H- pyrido[2,3-c]carbazolyl, 2-, 3-, 6-, or7-imidazo[1,2-b][1,2,4]triazinyl, 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, 2-, 4-, 4-, 5-, 6-,or 7-benzothiazolyl, 1-, 2-, 4-, 5-, 6-, 7-, 8-, or 9-benzoxapinyl, 2-,4-, 5-, 6-, 7-, or 8-benzoxazinyl, 1-, 2-, 3-, 5-, 6-, 7-, 8-, 9-, 10-,or 11-1H-pyrrolo[1,2-b][2]benzazapinyl. Typical fused heteroary groupsinclude, but are not limited to 2-, 3-, 4-, 5-, 6-, 7-, or 8-quinolinyl,1-, 3-, 4-, 5-, 6-, 7-, or 8-isoquinolinyl, 2-, 3-, 4-, 5-, 6-, or7-indolyl, 2-, 3-, 4-, 5-, 6-, or 7-benzo[b]thienyl, 2-, 4-, 5-, 6-, or7-benzoxazolyl, 2-, 4-, 5-, 6-, or 7-benzimidazolyl, and 2-, 4-, 5-, 6-,or 7-benzothiazolyl.

A heteroaryl group may be substituted with 1 to 5 substituentsindependently selected from the groups consisting of the following:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., ═O;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic groupbonded through an oxygen bridge;

(j) alkyl-O—C(O)—;

(k) mercapto;

(l) amido or carboxamido

(m) cyano;

(n) sulfamoyl, sulfamido or sulfonamido;

(o) aryl;

(p) alkyl-C(O)—O—;

(q) aryl-C(O)—O—;

(r) aryl-S—;

(s) aryloxy;

(t) alkyl-S—;

(u) formyl, i.e., HC(O)—;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

(y) alkyl substituted with cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

As used herein, the term “halogen” or “halo” refers to fluoro, chloro,bromo, and iodo.

As used herein, the term “optionally substituted” unless otherwisespecified refers to a group that is unsubstituted or is substituted byone or more, typically 1, 2, 3 or 4, suitable non-hydrogen substituents,each of which is independently selected from the group consisting of:

(a) alkyl;

(b) hydroxy (or protected hydroxy);

(c) halo;

(d) oxo, i.e., ═O;

(e) amino, alkylamino or dialkylamino;

(f) alkoxy;

(g) cycloalkyl;

(h) carboxyl;

(i) heterocyclooxy, wherein heterocyclooxy denotes a heterocyclic groupbonded through an oxygen bridge;

(j) alkyl-O—C(O)—;

(k) mercapto;

(l) amido or carboxamido

(m) cyano;

(n) sulfamoyl, sulfamido or sulfonamido;

(o) aryl;

(p) alkyl-C(O)—O—;

(q) aryl-C(O)—O—;

(r) aryl-S—;

(s) aryloxy;

(t) alkyl-S—;

(u) formyl, i.e., HC(O)—;

(v) carbamoyl;

(w) aryl-alkyl-; and

(x) aryl substituted with alkyl, cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

(y) alkyl substituted with cycloalkyl, alkoxy, hydroxy, amino,alkyl-C(O)—NH—, alkylamino, dialkylamino or halogen.

In one aspect, compounds of Formula (I) are provided:

1. A compound of formula (I):

or a salt thereof, wherein

m is 0, 1 or 2;

n is 0 or 1, wherein m+n is 1, 2 or 3;

R₁ is C₃-C₁₀alkynyl or phenyl, which phenyl is substituted with 0, 1, 2,or 3 substituents which are independently selected from the groupconsisting of halogen, hydroxy, cyano, C₁-C₄alkyl, haloC₁-C₄alkyl andC₁-C₄alkoxy, and which alkynyl is optionally substituted with aC₃-C₇cycloalkyl substituent, which cycloalkyl is optionally substitutedwith 1 or 2 independently selected C₁-C₄alkyl groups;

R₂ is CO₂H, tetrazole, C(O)N(H)S(O)₂CH₃ or a carboxylic acid isostere;

R₃ is C₃-C₇cycloalkyl which is substituted with 0, 1, 2 or 3 halogenatoms;

R_(3a) represents 0, 1, 2, 3 or 4 residues independently selected ateach occurrence from the group consisting of hydroxy, amino, cyano,halogen, C₁-C₆alkyl, C₁-C₆alkoxy, wherein each alkyl or alkoxysubstituent is substituted with 0, 1 or 2 substituents independentlyselected from hydroxy, cyano, C₁-C₄alkoxy, C₁-C₄alkylsulfone,N(R_(3b))₂, C(O)N(R_(3b)), heterocycle having 4 to 7 ring atoms and 1 or2 ring heteroatoms selected from N, O or S and 5 or 6 member heteroaryl;or two geminal R_(3a) substituents, taken in combination form aspirocyclic 3 to 6 member cycloalkyl or heterocycle;

R_(3b) is independently selected at each occurrence from hydrogen,C₁-C₄alkyl, C₁-C₄alkoxyC₁-C₄alkyl and C₁-C₄alkanoyl; or N(R_(3b))₂,taken in combination, form a 4 to 6 member heterocycle having 0 or 1additional ring heteroatoms selected from N, O or S;

X is O, N-L-R₄ or CR₅R₆;

L is a bond, S(O)₂, C(O) or C(O)O;

R₄ is C₁-C₆alkyl, C₃-C₇cycloalkyl or C₃-C₇cycloalkylC₁-C₄alkyl each ofwhich is substituted with 0, 1, or 2 hydroxy and 0 or 1 substituentsselected from cyano, S(O)₂—C₁-C₄alkyl, CO₂H, NR_(4a)R_(4b), phenyl orpyridyl, wherein the phenyl or pyridyl substituent is substituted with0, 1, or 2 substituents selected from C₁-C₄alkyl, halogen, NR_(4a)R_(4b)or 5 or 6 member heteroaryl having 1 or 2 ring nitrogen atoms;

R₄ is naphthyl or phenyl, which phenyl is substituted with 0, 1, 2, or 3substituents independently selected form the group consisting ofhalogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl, C₁-C₆alkoxy,haloC₁-C₆alkoxy, hydroxy, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₆alkyl-OC(O)NH—, C₁-C₄alkyl-C(O)NH—, NR_(4a)R_(4b). CO₂H,—C(O)NR_(4a)R_(4b), phenyl, phenoxy, heteroaryl having one or two ringnitrogen atoms and having 0, 1, or 2 C₁-C₄alkyl substituents, or twosubstituents combine to form a fused heterocyclic or heteroaryl ring,which fused heterocycle has 5, 6 or 7 ring atoms, has 1 or 2 ringheteroatoms selected from N, O or S, and which fused heterocycle issubstituted with 0, 1 or 2 substituents independently selected fromC₁-C₆alkyl or oxo and which fused heteroaryl has 5 or 6 ring atoms, has1 or 2 ring heteroatoms selected from N, O or S and which fusedheteroaryl is substituted with 0, 1, or 2 independently selectedC₁-C₄alkyl substituents; or

R₄ is a 5 or 6 member heteroaryl having 1 to 3 heteroatoms selected fromN, O or S, which heteroaryl is substituted with 0, 1, 2 or 3substituents independently selected from the group consisting ofhalogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl, C₁-C₆alkoxy,haloC₁-C₆alkoxy, hydroxy, NR_(4a)R_(4b), hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₁-C₆alkyl-OC(O)NH—, CO₂H, C₃-C₇cycloalkyl,C₅-C₇cycloalkenyl, phenyl, 5 or 6 membered heteroaryl having 1 or 2 ringheteroatoms selected from N, O or S, saturated or partially unsaturatedmonocyclic or bicyclic heterocycle or two substituents, taken incombination form a saturated heterocyclic ring having 5 or 6 ring atoms,1 or 2 ring heteroatoms selected from N, O or S and wherein the fusedheterocyle is substituted with 0, 1, or 2 independently selectedC₁-C₄alkyl substituents; and wherein the monocyclic or bicyclicheterocycle has 1 or 2 ring N, O or S atoms, 5 to 7 ring atoms in eachring and is substituted with 0, 1 or 2 substituents independentlyselected from the group consisting of halogen, C₁-C₆alkyl,C₁-C₆alkanoyl, C₁-C₆alkoxycarbonyl, C_(r) C₆alkoxyC(O)N(H)—,C₁-C₆alkoxyC(O)N(H)CH₂—, aminoC₁-C₄alkyl, C₁-C₄alkoxyC₁-C₄alkyl andNR_(4a)R_(4b), and wherein the phenyl or heteroaryl substituent issubstituted with 0, 1 or 2 independently selected substituents selectedfrom halogen, CO₂H, cyano, C₁-C₄alkyl, C₁-C₄alkoxy, NR_(4a)R_(4b),CH₂NR_(4a)R_(4b), C(O)NR_(4a)R_(4b), or two phenyl substituents combineto form a divalent —O—(CH₂)_(q)—O— substituent in which q is 1, 2, or 3;or

R₄ is a saturated heterocycle 1 ring nitrogen and 0 or 1 additional ringheteroatom selected from N, O or S, which heterocyclic ring issubstituted with 0, 1, or 2 substituents independently selected from thegroup consisting of C₁-C₆alkyl, CO₂C₁-C₆alkyl or CO₂benzyl;

R_(4a) is independently selected at each occurrence from the groupconsisting of hydrogen and C₁-C₆alkyl, wherein the alkyl substituent isunsubstituted or substituted with hydroxy, C₁-C₄alkoxy, amino or mono-and di-C₁-C₄alkylamino;

R_(4b) is independently selected at each occurrence from the groupconsisting of hydrogen, C₁-C₆alkyl, C₃-C₇cycloalkyl, C₁-C₄alkanoyl, andheterocycle having 4 to 7 ring atoms and 1 or 2 ring heteroatomsindependently selected at each occurrence from N, O or S, wherein thealkyl substituent is unsubstituted or substituted with hydroxy,C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino; or

NR_(4a)R_(4b), taken in combination, form a heterocyclic ring having onering nitrogen atom and 0 or 1 additional ring heteroatom selected fromN, O and S, which heterocyclic ring is substituted with 0, 1, 2 or 3substituents independently selected from the group consisting ofhalogen, hydroxy, oxo, amino, C₁-C₄alkyl, haloC₁-C₄alkyl,hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkanoyl,C₁-C₄alkoxyC₁-C₄alkyl, and mono- and di-C₁-C₄alkylamino;

R₅ is absent or is selected from the group consisting of hydrogen andC₁-C₆alkyl;

R₆ is oxo, hydrogen, hydroxy, amino, N(H)-J-R₇;

J is absent, C(O) or S(O)₂; and

R₇ is C₁-C₆alkyl, phenyl or benzyl, each of is optionally substitutedwith C₁-C₆alkyl, C_(r) C₆alkoxy, halogen, phenyl or phenoxy.

Certain compounds of formula (I) provided by the invention includecompounds of formula (Ia) and salts thereof:

wherein

-   R₁ is C₃-C₈alkynyl or phenyl, which phenyl is substituted with 0, 1,    2, or 3 substituents which are independently selected from the group    consisting of halogen, hydroxy, cyano, C₁-C₄alkyl and C₁-C₄alkoxy,    and which alkynyl is optionally substituted with a C₃-C₇cycloalkyl    substituent, which cycloalkyl is optionally substituted with 1 or 2    independently selected C₁-C₄alkyl groups;-   R_(3a) represents 0, 1, 2, 3 or 4 residues independently selected at    each occurrence from the group consisting of hydroxy, amino,    C₁-C₆alkyl, C₁-C₆alkoxy, wherein each alkyl or alkoxy substituent is    substituted with 0, 1 or 2 substituents independently selected from    hydroxy, C₁-C₄alkoxy, C₁-C₄alkylsulfoxide and N(R_(3b)); or two    geminal R_(3a) substituents, taken in combination form a spirocyclic    3 to 6 member cycloalkyl or heterocycle;-   R_(3b) is independently selected at each occurrence from hydrogen,    C₁-C₄alkyl, C₁-C₄alkoxyC₁-C₄alkyl, or N(R_(3b))₂, taken in    combination, form a 4 to 6 member heterocycle having 0 or 1    additional ring heteroatoms selected from N, O or S;-   X is O, N-L-R₄ or CR₅R₆;-   L is a bond, S(O)₂ or C(O);    -   R₄ is C₁-C₆alkyl or C₃-C₇cycloalkyl each of which is substituted        with 0 or 1 substituents selected from CO₂H or NR_(4a)R_(4b) or        C₁-C₄ alkylphenyl, or    -   R₄ is naphthyl or phenyl, which phenyl is substituted with 0, 1,        2, or 3 substituents independently selected form the group        consisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl,        C₁-C₆alkoxy, haloC₁-C₆alkoxy, amino, hydroxy, mono- and        di-C₁-C₆alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,        C₁-C₆alkyl-OC(O)NH—, C₁-C₄alkyl-C(O)NH—, —C(O)NR_(4a)R_(4b),        phenyl, phenoxy, heteroaryl having one or two ring nitrogen        atoms and having 0, 1, or 2 C₁-C₄alkyl substituents, or two        substituents combine to form a fused heterocyclic ring, which        heterocycle has 5, 6 or 7 ring atoms, 1 or 2 ring heteroatoms        selected from N, O or S and which heterocycle is substituted        with 0, 1 or 2 substituents independently selected from        C₁-C₆alkyl; or    -   R₄ is a 5 or 6 member heteroaryl having 1 to 3 heteroatoms        selected from N, O or S, which heteroaryl is substituted with 0,        1, or 2 substituents independently selected from the group        consisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl,        C₁-C₆alkoxy, haloC₁-C₆alkoxy, hydroxy, NR_(4a)R_(4b),        hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₆alkyl-OC(O)NH—,        C₃-C₇cycloalkyl, C₅-C₇cycloalkenyl, phenyl, thienyl optionally        substituted with CO₂H, or saturated or partially unsaturated        monocyclic or bicyclic heterocycle which heterocycle has 1 or 2        ring N, O or S atoms, 5 to 7 ring atoms in each ring and is        substituted with 0, 1 or 2 substituents independently selected        from the group consisting of C₁-C₆alkyl, C₁-C₆alkanoyl,        —N(H)C(O)C₁-C₆alkoxy, —CH₂N(H)C(O)C₁-C₆alkoxy, aminoC₁-C₄alkyl,        C₁-C₄alkoxyC₁-C₄alkyl and NR_(4a)R_(4b), or two substituents on        the heteroaryl ring combine to form a fused heterocyclic ring,        which heterocycle has 5, 6 or 7 ring atoms, 1 or 2 ring        heteroatoms selected from N, O or S and which heterocycle is        substituted with 0, 1 or 2 substituents independently selected        from C₁-C₆alkyl, and wherein the phenyl substituent is        unsubstituted or substituted with halogen, C₁-C₄alkyl, or        C(O)NR_(4a)R_(4b); or    -   R₄ is a saturated heterocycle 1 ring nitrogen and 1 or 1        additional ring heteroatom selected from N, O or S, which        heterocyclic ring is substituted with 0, 1, or 2 substituents        independently selected from the group consisting of C₁-C₆alkyl,        CO₂C₁-C₆alkyl or CO₂benzyl;    -   R_(4a) is independently selected at each occurrence from the        group consisting of hydrogen and C₁-C₆alkyl, wherein the alkyl        substituent is unsubstituted or substituted with hydroxy,        C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino;    -   R_(4b) is independently selected at each occurrence from the        group consisting of hydrogen, C₁-C₆alkyl and C₁-C₄alkanoyl,        wherein the alkyl substituent is unsubstituted or substituted        with hydroxy, C₁-C₄alkoxy, amino or mono- and        di-C₁-C₄alkylamino; or    -   NR_(4a)R_(4b), taken in combination, form a heterocyclic ring        having one ring nitrogen atom and 0 or 1 additional ring        heteroatom selected from N, O and S, which heterocyclic ring is        substituted with 0, 1, 2 or 3 substituents independently        selected from the group consisting of halogen, hydroxy, amino,        C₁-C₄alkyl, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,        C₁-C₄alkoxy, C₁-C₄alkoxyC₁-C₄alkyl, and mono- and        di-C₁-C₄alkylamino;-   R₅ is absent or is selected from the group consisting of hydrogen    and C₁-C₆alkyl;-   R₆ is oxo, hydrogen, hydroxy, amino, N(H)-J-R₇;-   J is absent, C(O) or S(O)₂; and-   R₇ is C₁-C₆alkyl, phenyl or benzyl, each of is optionally    substituted with C₁-C₆alkyl, C₁-C₆alkoxy, halogen, phenyl or    phenoxy.

In one aspect, compounds of formula (I) include compounds of formula(II) and salts thereof:

wherein

-   Z is CH or N;-   R₈ is selected from hydrogen, CO₂H, C₁-C₄alkyl, C—C₄alkoxy, cyano or    halogen;-   R₉ is selected from C₁-C₆alkyl, C₁-C₆alkoxy, phenyl, NR_(9a)R_(9b),    N(H)—C(O)—O—C₁-C₄alkyl, and heterocycle, wherein the heterocycle has    one or two rings, each ring having 5, 6, or 7 ring atoms, one ring    nitrogen atom and 0 or 1 additional ring heteroatom selected from N,    O or S, and wherein the heterocycle is unsubstituted or substituted    with 1, 2 or 3 substituents independently selected from the group    consisting of halogen, hydroxy, amino, C₁-C₄alkyl, haloC₁-C₄alkyl,    hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl, C₁-C₄alkoxy,    C₁-C₄alkoxyC₁-C₄alkyl, and mono- and di-C₁-C₄alkylamino; or-   R₈ and R₉, taken in combination form a divalent residue selected    from —O(CH₂)_(p)O—, —O(CH₂)₂NH—, or —O(CH₂)₂N(CH₃)—;    -   R_(9a) is selected from the group consisting of hydrogen and        C₁-C₆alkyl, wherein the alkyl substituent is unsubstituted or        substituted with hydroxy, C₁-C₄alkoxy, amino or mono- and        di-C₁-C₄alkylamino; and    -   R_(9b) is selected from the group consisting of hydrogen,        C₁-C₆alkyl and C₁-C₄alkanoyl, wherein the alkyl substituent is        unsubstituted or substituted with hydroxy, C₁-C₄alkoxy, amino or        mono- and di-C₁-C₄alkylamino.

In certain aspects, compounds of formula (II) include those compounds inwhich R₈ is selected from hydrogen, CO₂H, methyl, methoxy orhydroxymethyl.

Certain other compounds of formula (II) include those compounds in whichR₉ is selected from the group consisting of morpholino, piperidinyl,piperazinyl, and pyrrolidinyl, each of which is unsubstituted orsubstituted with one or two substituents selected from the groupconsisting of C₁-C₄alkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₄alkoxy, mono- and di-C₁-C₄alkylamino, and C₁-C₄alkoxycarbonyl.

Still other compounds of formula (II) include those compounds in which Zis N.

In yet other aspects, compounds of formula (II) include those compoundsin which

-   R₈ is selected from hydrogen, CO₂H, methyl, methoxy or    hydroxymethyl;-   R₉ is selected from the group consisting of morpholino, piperidinyl,    piperazinyl, and pyrrolidinyl, each of which is unsubstituted or    substituted with one or two substituents selected from the group    consisting of C₁-C₄alkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,    C₁-C₄alkoxy, mono- and di-C₁-C₄alkylamino, and C₁-C₄alkoxycarbonyl;    and Z is N.    In certain aspects, compounds of formula (I), (la) or (II) include    compounds of formula (IIa) and salts thereof

Wherein

-   Y is a bond, O, NR₁₇, or CR₁₇R₁₈;-   R_(1a) is H, F, Cl or CH₃-   R₈ is hydrogen, methyl, CO₂H, or methoxy;-   R₁₃ and R₁₄, are each independently selected from hydrogen or    C₁-C₄alkyl;-   R₁₅ and R₁₆, are each independently selected from hydrogen,    C₁-C₄alkyl, hydroxyC₁-C₄alkyl, amino, or mono- and di    C₁-C₄alkylamino;-   R₁₇ is selected from hydrogen, C₁-C₄alkyl, or C₁-C₄alkoxycarbonyl;    and-   R₁₈ is selected from hydrogen, C₁-C₄alkyl, C₁-C₄alkoxy, amino, or    amino C₁-C₄alkyl.

In another aspect, compounds of formula (I) include compounds of formula(III) and salts thereof:

wherein

-   R₆ is hydrogen, hydroxy, amino or N(H)-J-R₇;-   J is C(O) or S(O)₂;-   R₇ is (a) C₁-C₄alkyl optionally substituted with phenyl or phenoxy,    or    -   (b) phenyl optionally substituted with C₁-C₄alkyl, halogen or        C₁-C₄alkoxy;-   R₁₀ is selected from hydrogen and C₁-C₆alkyl which alkyl is    unsubstituted or substituted with one or two substituents selected    from OH, cyano, SO₂CH₃, methoxy, ethoxy, N(R_(10a))₂ and    C(O)(NR_(10a))₂;-   R_(10a) is selected at each occurrence from the group consisting of    hydrogen and C₁-C₄alkyl which is substituted with 0 or 1    substituents selected from hydroxy, methoxy or ethoxy;-   R₁₁ is selected from the group consisting of hydrogen, fluoro,    hydroxy and C₁-C₄alkyl.

In another aspect, compounds of formula (III) include those compounds inwhich R₁₀ is hydrogen or C₁-C₆alkyl substituted with one or two hydroxysubstituents or one substitutent independently selected from the groupconsisting of cyano, SO₂CH₃, methoxy, ethoxy, amino, mono- anddi-C₁-C₂alkylamino, C(O)NH₂, C(O)N(H)Me and C(O)NMe₂. In certain othercompounds of formula (III), R₁₀ is C₁-C₆alkyl substituted with one ortwo hydroxy substituents or one substitutent independently selected fromthe group consisting of cyano, SO₂CH₃, methoxy, ethoxy, amino, or mono-and di-C₁-C₂alkylamino.

In yet another aspect, compounds of formula (I) include compounds offormula (IV) and salts thereof:

wherein

-   R₁₀, R₁₁ is independently selected from hydrogen and C₁-C₆alkyl    which alkyl is unsubstituted or substituted with one or two    substituents selected from OH, SO₂CH₃, cyano, methoxy, ethoxy,    N(R_(10a))₂ and C(O)N(R_(10a))₂;-   R_(10a) is selected at each occurrence from the group consisting of    hydrogen and C₁-C₄alkyl which is substituted with 0 or 1    substituents selected from hydroxy, methoxy or ethoxy;-   Or N(R_(10a))₂ could form a 3-6 member cycloakyl or heterocycle-   R₁₂ is selected from the group consisting of hydrogen and    C₁-C₄alkyl.

In another aspect, compounds of formula (IV) include those compounds inwhich R₁₀ is hydrogen or C₁-C₆alkyl substituted with one or two hydroxysubstituents or one substitutent independently selected from the groupconsisting of cyano, SO₂CH₃, methoxy, ethoxy, amino, mono- anddi-C₁-C₂alkylamino, C(O)NH₂, C(O)N(H)Me and C(O)NMe₂. In certain othercompounds of formula (IV), R₁₀ is C₁-C₆alkyl substituted with one or twohydroxy substituents or one substitutent independently selected from thegroup consisting of cyano, SO₂CH₃, methoxy, ethoxy, amino, or mono- anddi-C₁-C₂alkylamino.

In one aspect, compounds of formula (I), (Ia), (II), (IIa), (Ill) or(IV) include those compounds in which R₁ is tert-butylethynyl, phenyl,or phenyl para-substituted with F, Cl, or methyl. In certain instances,compounds of the identified formulae include those compounds in which R₁is phenyl or tert-butylethynyl. In certain other compounds of formula(I), (Ia), (II), (IIa), (Ill), and/or (IV), R₁ is phenyl. In still othercompounds of formula (I), (Ia), (II), (IIa), (Ill), and/or (IV), R₁ istert-butylethynyl.

In another aspect, compounds of formula (I), (II), (IIa), (Ill) or (IV)include those compounds in which R₂ is CO₂H.

In one aspect, compounds of formula (I), (Ia), (II), (IIa), (III) or(IV) include those compounds in which R₃ is cyclohexyl.

In yet another aspect, compounds of (III) include those compounds inwhich R₆ is hydrogen;

-   R₁₀ is hydrogen or hydoxyC₁-C₆alkyl; and-   R₁₁ is hydrogen, methyl, hydroxy or fluoro.

In yet another aspect, compounds of (III) include those compounds inwhich R₆ is hydrogen;

-   R₁₀ is hydoxyC₁-C₆alkyl; and-   R₁₁ is hydrogen, methyl, hydroxy or fluoro.

In yet another aspect, compounds of (IV) include those compounds inwhich R₁₀ is hydoxyC₁-C₆alkyl;

-   R₁₁ is hydrogen or methyl; and-   R₁₂ is hydrogen or methyl.

In certain aspects, compounds of formula (III) are provided in which R₁is tert-butylethynyl, phenyl, or phenyl para-substituted with F, Cl, ormethyl;

R₂ is CO₂H;

R₃ is cyclohexyl;

R₆ is hydrogen;

R₁₀ is hydroxyC₁-C₆alkyl; and

R₁₁ is hydrogen, hydroxy, methyl or fluoro.

In certain aspects, compounds of formula (III) are provided in which R₁is tert-butylethynyl;

R₂ is CO₂H;

R₃ is cyclohexyl;

R₆ is hydrogen;

R₁₀ is hydroxyC₁-C₆alkyl; and

R₁₁ is hydrogen, hydroxy, methyl or fluoro.

In certain aspects, compounds of formula (IV) are provided in which R₁is tert-butylethynyl;

R₂ is CO₂H;

R₃ is cyclohexyl;

R₁₀ is hydroxyC₁-C₆alkyl; and

R₁₁ and R₁₂ are independently selected from the group consisting of ishydrogen and methyl.

In certain other aspects, the invention provides compounds of Formula(V)

or a salt thereof, wherein

R₁₁ is hydrogen or methyl;

R₁₀ is C₂-C₆hydroxyalkyl wherein the hydroxyl group is a primary,secondary or tertiary alcohol. For example R₁₀ is selected from—(CH₂)_(a)OH, —(CH₂)_(b)CH(CH₃)OH or —(CH₂)_(b)C(CH₃)₂OH, wherein a is2, 3, or 4 and b is 1, 2, or 3. In certain compounds of Formula (V) a is2 or 3 and b is 1 or 2.

As used herein, the term “isomers” refers to different compounds thathave the same molecular formula but differ in arrangement andconfiguration of the atoms. Also as used herein, the term “an opticalisomer” or “a stereoisomer” refers to any of the various stereo isomericconfigurations which may exist for a given compound of the presentinvention and includes geometric isomers. It is understood that asubstituent may be attached at a chiral center of a carbon atom.Therefore, the invention includes enantiomers, diastereomers orracemates of the compound. “Enantiomers” are a pair of stereoisomersthat are non-superimposable mirror images of each other. A 1:1 mixtureof a pair of enantiomers is a “racemic” mixture. The term is used todesignate a racemic mixture where appropriate. “Diastereoisomers” arestereoisomers that have at least two asymmetric atoms, but which are notmirror-images of each other. The absolute stereochemistry is specifiedaccording to the Cahn-Ingold-Prelog R-S system. When a compound is apure enantiomer the stereochemistry at each chiral carbon may bespecified by either R or S. Resolved compounds whose absoluteconfiguration is unknown can be designated (+) or (−) depending on thedirection (dextro- or levorotatory) which they rotate plane polarizedlight at the wavelength of the sodium D line. Certain of the compoundsdescribed herein contain one or more asymmetric centers or axes and maythus give rise to enantiomers, diastereomers, and other stereoisomericforms that may be defined, in terms of absolute stereochemistry, as (R)-or (S)-. The present invention is meant to include all such possibleisomers, including racemic mixtures, optically pure forms andintermediate mixtures. Optically active (R)- and (S)-isomers may beprepared using chiral synthons or chiral reagents, or resolved usingconventional techniques. If the compound contains a double bond, thesubstituent may be E or Z configuration. If the compound contains adisubstituted cycloalkyl, the cycloalkyl substituent may have a cis- ortrans-configuration. All tautomeric forms are also intended to beincluded.

As used herein, the terms “salt” or “salts” refers to an acid additionor base addition salt of a compound of the invention. “Salts” include inparticular “pharmaceutical acceptable salts”. The term “pharmaceuticallyacceptable salts” refers to salts that retain the biologicaleffectiveness and properties of the compounds of this invention and,which typically are not biologically or otherwise undesirable. In manycases, the compounds of the present invention are capable of formingacid and/or base salts by virtue of the presence of amino and/orcarboxyl groups or groups similar thereto.

Pharmaceutically acceptable acid addition salts can be formed withinorganic acids and organic acids, e.g., acetate, aspartate, benzoate,besylate, bromide/hydrobromide, bicarbonate/carbonate,bisulfate/sulfate, cam phorsulfornate, chloride/hydrochloride,chlortheophyllonate, citrate, ethandisulfonate, fumarate, gluceptate,gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate,lactate, lactobionate, laurylsulfate, malate, maleate, malonate,mandelate, mesylate, methylsulphate, naphthoate, napsylate, nicotinate,nitrate, octadecanoate, oleate, oxalate, palmitate, pamoate,phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate,propionate, stearate, succinate, sulfosalicylate, tartrate, tosylate andtrifluoroacetate salts.

Inorganic acids from which salts can be derived include, for example,hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid, and the like.

Organic acids from which salts can be derived include, for example,acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid,malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid,benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid,toluenesulfonic acid, sulfosalicylic acid, and the like.Pharmaceutically acceptable base addition salts can be formed withinorganic and organic bases.

Inorganic bases from which salts can be derived include, for example,ammonium salts and metals from columns I to XII of the periodic table.In certain embodiments, the salts are derived from sodium, potassium,ammonium, calcium, magnesium, iron, silver, zinc, and copper;particularly suitable salts include ammonium, potassium, sodium, calciumand magnesium salts.

Organic bases from which salts can be derived include, for example,primary, secondary, and tertiary amines, substituted amines includingnaturally occurring substituted amines, cyclic amines, basic ionexchange resins, and the like. Certain organic amines includeisopropylamine, benzathine, cholinate, diethanolamine, diethylamine,lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the present invention can besynthesized from a parent compound, a basic or acidic moiety, byconventional chemical methods. Generally, such salts can be prepared byreacting free acid forms of these compounds with a stoichiometric amountof the appropriate base (such as Na, Ca, Mg, or K hydroxide, carbonate,bicarbonate or the like), or by reacting free base forms of thesecompounds with a stoichiometric amount of the appropriate acid. Suchreactions are typically carried out in water or in an organic solvent,or in a mixture of the two. Generally, use of non-aqueous media likeether, ethyl acetate, ethanol, isopropanol, or acetonitrile isdesirable, where practicable. Lists of additional suitable salts can befound, e.g., in “Remington's Pharmaceutical Sciences”, 20th ed., MackPublishing Company, Easton, Pa., (1985); and in “Handbook ofPharmaceutical Salts: Properties, Selection, and Use” by Stahl andWermuth (Wiley-VCH, Weinheim, Germany, 2002).

Any formula given herein is also intended to represent unlabeled formsas well as isotopically labeled forms of the compounds. Isotopicallylabeled compounds have structures depicted by the formulas given hereinexcept that one or more atoms are replaced by an atom having a selectedatomic mass or mass number. Examples of isotopes that can beincorporated into compounds of the invention include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, and chlorine,such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C, ¹⁵N, ¹⁸F, ³¹P, ³²P, ³⁵S, ³⁶Cl, ¹²⁵Irespectively. The invention includes various isotopically labeledcompounds as defined herein, for example those into which radioactiveisotopes, such as ³H, ¹³C, and ¹⁴C, are present. Such isotopicallylabelled compounds are useful in metabolic studies (with ¹⁴C), reactionkinetic studies (with, for example ²H or ³H), detection or imagingtechniques, such as positron emission tomography (PET) or single-photonemission computed tomography (SPECT) including drug or substrate tissuedistribution assays, or in radioactive treatment of patients. Inparticular, an ¹⁸F or labeled compound may be particularly desirable forPET or SPECT studies. Isotopically labeled compounds of this inventionand prodrugs thereof can generally be prepared by carrying out theprocedures disclosed in the schemes or in the examples and preparationsdescribed below by substituting a readily available isotopically labeledreagent for a non-isotopically labeled reagent.

Further, substitution with heavier isotopes, particularly deuterium(i.e., ²H or D) may afford certain therapeutic advantages resulting fromgreater metabolic stability, for example increased in vivo half-life orreduced dosage requirements or an improvement in therapeutic index. Itis understood that deuterium in this context is regarded as asubstituent of a compound of the formula (I). The concentration of sucha heavier isotope, specifically deuterium, may be defined by theisotopic enrichment factor. The term “isotopic enrichment factor” asused herein means the ratio between the isotopic abundance and thenatural abundance of a specified isotope. If a substituent in a compoundof this invention is denoted deuterium, such compound has an isotopicenrichment factor for each designated deuterium atom of at least 3500(52.5% deuterium incorporation at each designated deuterium atom), atleast 4000 (60% deuterium incorporation), at least 4500 (67.5% deuteriumincorporation), at least 5000 (75% deuterium incorporation), at least5500 (82.5% deuterium incorporation), at least 6000 (90% deuteriumincorporation), at least 6333.3 (95% deuterium incorporation), at least6466.7 (97% deuterium incorporation), at least 6600 (99% deuteriumincorporation), or at least 6633.3 (99.5% deuterium incorporation).

Isotopically-labeled compounds of formula (I) can generally be preparedby conventional techniques known to those skilled in the art or byprocesses analogous to those described in the accompanying Examples andPreparations using an appropriate isotopically-labeled reagent& in placeof the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Compounds of the invention, i.e. compounds of formula (I) that containgroups capable of acting as donors and/or acceptors for hydrogen bondsmay be capable of forming co-crystals with suitable co-crystal formers.These co-crystals may be prepared from compounds of formula (I) by knownco-crystal forming procedures. Such procedures include grinding,heating, co-subliming, co-melting, or contacting in solution compoundsof formula (I) with the co-crystal former under crystallizationconditions and isolating co-crystals thereby formed. Suitable co-crystalformers include those described in WO 2004/078163. Hence the inventionfurther provides co-crystals comprising a compound of formula (I).

As used herein, the term “pharmaceutically acceptable carrier” includesany and all solvents, dispersion media, coatings, surfactants,antioxidants, preservatives (e.g., antibacterial agents, antifungalagents), isotonic agents, absorption delaying agents, salts,preservatives, drugs, drug stabilizers, binders, excipients,disintegration agents, lubricants, sweetening agents, flavoring agents,dyes, and the like and combinations thereof, as would be known to thoseskilled in the art (see, for example, Remington's PharmaceuticalSciences, 18th Ed. Mack Printing Company, 1990, pp. 1289-1329). Exceptinsofar as any conventional carrier is incompatible with the activeingredient, its use in the therapeutic or pharmaceutical compositions iscontemplated.

The term “a therapeutically effective amount” of a compound of thepresent invention refers to an amount of the compound of the presentinvention that will elicit the biological or medical response of asubject, for example, reduction or inhibition of an enzyme or a proteinactivity, or ameliorate symptoms, alleviate conditions, slow or delaydisease progression, or prevent a disease, etc. In one non-limitingembodiment, the term “a therapeutically effective amount” refers to theamount of the compound of the present invention that, when administeredto a subject, is effective to (1) at least partially alleviating,inhibiting, preventing and/or ameliorating a condition, or a disorder ora disease (i) mediated by HCV infection, or (ii) associated with HCVinfection; or (2) reducing or inhibiting the viral replication or viralload of HCV. In another non-limiting embodiment, the term “atherapeutically effective amount” refers to the amount of the compoundof the present invention that, when administered to a cell, or a tissue,or a non-cellular biological material, or a medium, is effective to atleast partially reducing or inhibiting the activity of NS5b; or at leastpartially reducing or inhibiting the replication of HCV.

As used herein, the term “subject” refers to an animal. Typically theanimal is a mammal. A subject also refers to for example, primates(e.g., humans, male or female), cows, sheep, goats, horses, dogs, cats,rabbits, rats, mice, fish, birds and the like. In certain embodiments,the subject is a primate. In yet other embodiments, the subject is ahuman.

As used herein, the term “inhibit”, “inhibition” or “inhibiting” refersto the reduction or suppression of a given condition, symptom, ordisorder, or disease, or a significant decrease in the baseline activityof a biological activity or process.

As used herein, the term “treat”, “treating” or “treatment” of anydisease or disorder refers in one embodiment, to ameliorating thedisease or disorder (i.e., slowing or arresting or reducing thedevelopment of the disease or at least one of the clinical symptomsthereof). In another embodiment “treat”, “treating” or “treatment”refers to alleviating or ameliorating at least one physical parameterincluding those which may not be discernible by the patient. In yetanother embodiment, “treat”, “treating” or “treatment” refers tomodulating the disease or disorder, either physically, (e.g.,stabilization of a discernible symptom), physiologically, (e.g.,stabilization of a physical parameter), or both. In yet anotherembodiment, “treat”, “treating” or “treatment” refers to preventing ordelaying the onset or development or progression of the disease ordisorder.

As used herein, a subject is “in need of” a treatment if such subjectwould benefit biologically, medically or in quality of life from suchtreatment.

As used herein, the term “a,” “an,” “the” and similar terms used in thecontext of the present invention (especially in the context of theclaims) are to be construed to cover both the singular and plural unlessotherwise indicated herein or clearly contradicted by the context.

All methods described herein can be performed in any suitable orderunless otherwise indicated herein or otherwise clearly contradicted bycontext. The use of any and all examples, or exemplary language (e.g.“such as”) provided herein is intended merely to better illuminate theinvention and does not pose a limitation on the scope of the inventionotherwise claimed.

Any asymmetric atom (e.g., carbon or the like) of the compound(s) of thepresent invention can be present in racemic or enantiomericallyenriched, for example the (R)-, (S)- or (R,S)-configuration. In certainembodiments, each asymmetric atom has at least 50% enantiomeric excess,at least 60% enantiomeric excess, at least 70% enantiomeric excess, atleast 80% enantiomeric excess, at least 90% enantiomeric excess, atleast 95% enantiomeric excess, or at least 99% enantiomeric excess inthe (R)- or (S)-configuration. Substituents at atoms with unsaturatedbonds may, if possible, be present in cis-(Z)- or trans-(E)-form.

Accordingly, as used herein a compound of the present invention can bein the form of one of the possible isomers, rotamers, atropisomers,tautomers or mixtures thereof, for example, as substantially puregeometric (cis or trans) isomers, diastereomers, optical isomers(antipodes), racemates or mixtures thereof.

Any resulting mixtures of isomers can be separated on the basis of thephysicochemical differences of the constituents, into the pure orsubstantially pure geometric or optical isomers, diastereomers,racemates, for example, by chromatography and/or fractionalcrystallization.

Any resulting racemates of final products or intermediates can beresolved into the optical antipodes by known methods, e.g., byseparation of the diastereomeric salts thereof, obtained with anoptically active acid or base, and liberating the optically activeacidic or basic compound. In particular, a basic moiety may thus beemployed to resolve the compounds of the present invention into theiroptical antipodes, e.g., by fractional crystallization of a salt formedwith an optically active acid, e.g., tartaric acid, dibenzoyl tartaricacid, diacetyl tartaric acid, di-O,O′-p-toluoyl tartaric acid, mandelicacid, malic acid or camphor-10-sulfonic acid. Racemic products can alsobe resolved by chiral chromatography, e.g., high pressure liquidchromatography (HPLC) using a chiral adsorbent.

Compounds of the present invention are either obtained in the free form,as a salt thereof, or as prodrug derivatives thereof.

When both a basic group and an acid group are present in the samemolecule, the compounds of the present invention may also form internalsalts, e.g., zwitterionic molecules.

The present invention also provides pro-drugs of the compounds of thepresent invention that converts in vivo to the compounds of the presentinvention. A pro-drug is an active or inactive compound that is modifiedchemically through in vivo physiological action, such as hydrolysis,metabolism and the like, into a compound of this invention followingadministration of the prodrug to a subject. The suitability andtechniques involved in making and using pro-drugs are well known bythose skilled in the art. Prodrugs can be conceptually divided into twonon-exclusive categories, bioprecursor prodrugs and carrier prodrugs.See The Practice of Medicinal Chemistry, Ch. 31-32 (Ed. Wermuth,Academic Press, San Diego, Calif., 2001). Generally, bioprecursorprodrugs are compounds, which are inactive or have low activity comparedto the corresponding active drug compound, that contain one or moreprotective groups and are converted to an active form by metabolism orsolvolysis. Both the active drug form and any released metabolicproducts should have acceptably low toxicity.

Carrier prodrugs are drug compounds that contain a transport moiety,e.g., that improve uptake and/or localized delivery to a site(s) ofaction. Desirably for such a carrier prodrug, the linkage between thedrug moiety and the transport moiety is a covalent bond, the prodrug isinactive or less active than the drug compound, and any releasedtransport moiety is acceptably non-toxic. For prodrugs where thetransport moiety is intended to enhance uptake, typically the release ofthe transport moiety should be rapid. In other cases, it is desirable toutilize a moiety that provides slow release, e.g., certain polymers orother moieties, such as cyclodextrins. Carrier prodrugs can, forexample, be used to improve one or more of the following properties:increased lipophilicity, increased duration of pharmacological effects,increased site-specificity, decreased toxicity and adverse reactions,and/or improvement in drug formulation (e.g., stability, watersolubility, suppression of an undesirable organoleptic or physiochemicalproperty). For example, lipophilicity can be increased by esterificationof (a) hydroxyl groups with lipophilic carboxylic acids (e.g., acarboxylic acid having at least one lipophilic moiety), or (b)carboxylic acid groups with lipophilic alcohols (e.g., an alcohol havingat least one lipophilic moiety, for example aliphatic alcohols).

Exemplary prodrugs are, e.g., esters of free carboxylic acids and S-acylderivatives of thiols and O-acyl derivatives of alcohols or phenols,wherein acyl has a meaning as defined herein. Suitable prodrugs areoften pharmaceutically acceptable ester derivatives convertible bysolvolysis under physiological conditions to the parent carboxylic acid,e.g., lower alkyl esters, cycloalkyl esters, lower alkenyl esters,benzyl esters, mono- or di-substituted lower alkyl esters, such as the-(amino, mono- or di-lower alkylamino, carboxy, loweralkoxycarbonyl)-lower alkyl esters, the -(lower alkanoyloxy, loweralkoxycarbonyl or di-lower alkylaminocarbonyl)-lower alkyl esters, suchas the pivaloyloxymethyl ester and the like conventionally used in theart. In addition, amines have been masked as arylcarbonyloxymethylsubstituted derivatives which are cleaved by esterases in vivo releasingthe free drug and formaldehyde (Bundgaard, J. Med. Chem. 2503 (1989)).Moreover, drugs containing an acidic NH group, such as imidazole, imide,indole and the like, have been masked with N-acyloxymethyl groups(Bundgaard, Design of Prodrugs, Elsevier (1985)). Hydroxy groups havebeen masked as esters and ethers. EP 039,051 (Sloan and Little)discloses Mannich-base hydroxamic acid prodrugs, their preparation anduse.

Furthermore, the compounds of the present invention, including theirsalts, can also be obtained in the form of their hydrates, or includeother solvents used for their crystallization. The compounds of thepresent invention may inherently or by design form solvates withpharmaceutically acceptable solvents (including water); therefore, it isintended that the invention embrace both solvated and unsolvated forms.The term “solvate” refers to a molecular complex of a compound of thepresent invention (including pharmaceutically acceptable salts thereof)with one or more solvent molecules. Such solvent molecules are thosecommonly used in the pharmaceutical art, which are known to be innocuousto the recipient, e.g., water, ethanol, and the like. The term “hydrate”refers to the complex where the solvent molecule is water.

The compounds of the present invention, including salts, hydrates andsolvates thereof, may inherently or by design form polymorphs.

In another aspect, the present invention provides a pharmaceuticalcomposition comprising a compound of the present invention and apharmaceutically acceptable carrier. The pharmaceutical composition canbe formulated for particular routes of administration such as oraladministration, parenteral administration, and rectal administration,etc. In addition, the pharmaceutical compositions of the presentinvention can be made up in a solid form (including without limitationcapsules, tablets, pills, granules, powders or suppositories), or in aliquid form (including without limitation solutions, suspensions oremulsions). The pharmaceutical compositions can be subjected toconventional pharmaceutical operations such as sterilization and/or cancontain conventional inert diluents, lubricating agents, or bufferingagents, as well as adjuvants, such as preservatives, stabilizers,wetting agents, emulsifers and buffers, etc.

Typically, the pharmaceutical compositions are tablets or gelatincapsules comprising the active ingredient together with

-   -   a) diluents, e.g., lactose, dextrose, sucrose, mannitol,        sorbitol, cellulose and/or glycine;    -   b) lubricants, e.g., silica, talcum, stearic acid, its magnesium        or calcium salt and/or polyethyleneglycol; for tablets also    -   c) binders, e.g., magnesium aluminum silicate, starch paste,        gelatin, tragacanth, methylcellulose, sodium        carboxymethylcellulose and/or polyvinylpyrrolidone; if desired    -   d) disintegrants, e.g., starches, agar, alginic acid or its        sodium salt, or effervescent mixtures; and/or    -   e) absorbents, colorants, flavors and sweeteners.

Tablets may be either film coated or enteric coated according to methodsknown in the art.

Suitable compositions for oral administration include an effectiveamount of a compound of the invention in the form of tablets, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsion,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use are prepared according to any method known in the art for themanufacture of pharmaceutical compositions and such compositions cancontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets may contain the active ingredient in admixturewith nontoxic pharmaceutically acceptable excipients which are suitablefor the manufacture of tablets. These excipients are, for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for example,starch, gelatin or acacia; and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets are uncoated or coated byknown techniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate can be employed. Formulations fororal use can be presented as hard gelatin capsules wherein the activeingredient is mixed with an inert solid diluent, for example, calciumcarbonate, calcium phosphate or kaolin, or as soft gelatin capsuleswherein the active ingredient is mixed with water or an oil medium, forexample, peanut oil, liquid paraffin or olive oil.

Certain injectable compositions are aqueous isotonic solutions orsuspensions, and suppositories are advantageously prepared from fattyemulsions or suspensions. Said compositions may be sterilized and/orcontain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. In addition, they may also contain othertherapeutically valuable substances. Said compositions are preparedaccording to conventional mixing, granulating or coating methods,respectively, and contain about 0.1-75%, or contain about 1-50%, of theactive ingredient.

Suitable compositions for transdermal application include an effectiveamount of a compound of the invention with a suitable carrier. Carrierssuitable for transdermal delivery include absorbable pharmacologicallyacceptable solvents to assist passage through the skin of the host. Forexample, transdermal devices are in the form of a bandage comprising abacking member, a reservoir containing the compound optionally withcarriers, optionally a rate controlling barrier to deliver the compoundof the skin of the host at a controlled and predetermined rate over aprolonged period of time, and means to secure the device to the skin.

Suitable compositions for topical application, e.g., to the skin andeyes, include aqueous solutions, suspensions, ointments, creams, gels orsprayable formulations, e.g., for delivery by aerosol or the like. Suchtopical delivery systems will in particular be appropriate for dermalapplication, e.g., for the treatment of skin cancer, e.g., forprophylactic use in sun creams, lotions, sprays and the like. They arethus particularly suited for use in topical, including cosmetic,formulations well-known in the art. Such may contain solubilizers,stabilizers, tonicity enhancing agents, buffers and preservatives.

As used herein a topical application may also pertain to an inhalationor to an intranasal application. They may be conveniently delivered inthe form of a dry powder (either alone, as a mixture, for example a dryblend with lactose, or a mixed component particle, for example withphospholipids) from a dry powder inhaler or an aerosol spraypresentation from a pressurised container, pump, spray, atomizer ornebuliser, with or without the use of a suitable propellant.

The present invention further provides anhydrous pharmaceuticalcompositions and dosage forms comprising the compounds of the presentinvention as active ingredients, since water may facilitate thedegradation of certain compounds.

Anhydrous pharmaceutical compositions and dosage forms of the inventioncan be prepared using anhydrous or low moisture containing ingredientsand low moisture or low humidity conditions. An anhydrous pharmaceuticalcomposition may be prepared and stored such that its anhydrous nature ismaintained. Accordingly, anhydrous compositions are packaged usingmaterials known to prevent exposure to water such that they can beincluded in suitable formulary kits. Examples of suitable packaginginclude, but are not limited to, hermetically sealed foils, plastics,unit dose containers (e. g., vials), blister packs, and strip packs.

The invention further provides pharmaceutical compositions and dosageforms that comprise one or more agents that reduce the rate by which thecompound of the present invention as an active ingredient willdecompose. Such agents, which are referred to herein as “stabilizers,”include, but are not limited to, antioxidants such as ascorbic acid, pHbuffers, or salt buffers, etc.

The compounds of formula I in free form or in salt form, exhibitvaluable pharmacological properties, e.g NS5b inhibitory properties,e.g. as indicated in in vitro and in vivo tests as provided in the nextsections and are therefore indicated for therapy.

In one embodiment, the invention provides a method of treating anHCV-associated disorder comprising administering to a subject in needthereof a pharmaceutically acceptable amount of a compound of theinvention, such that the HCV-associated disorder is treated.

In another embodiment, the invention provides a method of treating anHIV infection comprising administering to a subject in need thereof apharmaceutically acceptable amount of a compound of the invention.

In still another embodiment, the invention provides a method oftreating, inhibiting or preventing the activity of HCV in a subject inneed thereof, comprising administering to the subject a pharmaceuticallyacceptable amount of a compound of the invention. In one embodiment, thecompounds of the invention inhibit the activity of the NS2 protease, theNS3 protease, the NS3 helicase, the NS5a protein, and/or the NS5bpolymerase. In another embodiment, the interaction between the NS3protease and NS4A cofactor is disrupted. In yet another embodiment, thecompounds of the invention prevent or alter the severing of one or moreof the NS4A-NS4B, NS4B-NS5A and NS5A-NS5B junctions of the HCV. Inanother embodiment, the invention provides a method of inhibiting theactivity of a serine protease, comprising the step of contacting saidserine protease with a compound of the invention. In another embodiment,the invention provides a method of treating, inhibiting or preventingthe activity of HCV in a subject in need thereof, comprisingadministering to the subject a pharmaceutically acceptable amount of acompound of the invention, wherein the compound interacts with anytarget in the HCV life cycle. In one embodiment, the target of the HCVlife cycle is selected from the group consisting of NS2 protease, NS3protease, NS3 helicase, NS5a protein and NS5b polymerase.

In another embodiment, the invention provides a method of decreasing theHCV RNA load in a subject in need thereof comprising administering tothe subject a pharmaceutically acceptable amount of a compound of theinvention.

In another embodiment, the compounds of the invention exhibit HCVprotease activity. In one embodiment, the compounds are an HCV NS3-4Aprotease inhibitor.

In another embodiment, the invention provides a method of treating anHCV-associated disorder in a subject, comprising administering to asubject in need thereof a pharmaceutically acceptable amount of acompound of the invention, and a pharmaceutically acceptable carrier,such that the HCV-associated disorder is treated.

In still another embodiment, the invention provides a method of treatingan HCV-associated disorder comprising administering to a subject in needthereof a pharmaceutically effective amount of a compound of theinvention, in combination with a pharmaceutically effective amount of anadditional HCV-modulating compound, such as interferon or derivatizedinterferon, or a cytochrome P450 monooxygenase inhibitor, such that theHCV-associated disorder is treated. In one embodiment, the additionalHCV-modulating compound is selected from the group consisting of NIM811,ITMN191, MK-7009, TMC 435350, Sch 503034 and VX-950.

In another embodiment, the invention provides a method of inhibitinghepatitis C virus replication in a cell, comprising contacting said cellwith a compound of the invention.

In yet another embodiment, the invention provides a packagedHCV-associated disorder treatment, comprising an HCV-modulating compoundof the invention, packaged with instructions for using an effectiveamount of the HCV-modulating compound to treat an HCV-associateddisorder.

In certain embodiments, the HCV-associated disorder is selected from thegroup consisting of HCV infection, liver cirrhosis, chronic liverdisease, hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin'slymphoma, liver fibrosis and a suppressed innate intracellular immuneresponse.

In another embodiment, the invention provides a method of treating HCVinfection, liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, liver fibrosisand/or a suppressed innate intracellular immune response in subject inneed thereof comprising administering to the subject a pharmaceuticallyacceptable amount of a compound of the invention.

In one embodiment, the HCV to be treated is selected of any HCVgenotype. In another embodiment, the HCV is selected from HCV genotype1, 2 and/or 3.

The pharmaceutical composition or combination of the present inventioncan be in unit dosage of about 1-1000 mg of active ingredient(s) for asubject of about 50-70 kg, or about 1-500 mg or about 1-250 mg or about1-150 mg or about 0.5-100 mg, or about 1-50 mg of active ingredients.The therapeutically effective dosage of a compound, the pharmaceuticalcomposition, or the combinations thereof, is dependent on the species ofthe subject, the body weight, age and individual condition, the disorderor disease or the severity thereof being treated. A physician, clinicianor veterinarian of ordinary skill can readily determine the effectiveamount of each of the active ingredients necessary to prevent, treat orinhibit the progress of the disorder or disease.

The above-cited dosage properties are demonstrable in vitro and in vivotests using advantageously mammals, e.g., mice, rats, dogs, monkeys orisolated organs, tissues and preparations thereof. The compounds of thepresent invention can be applied in vitro in the form of solutions,e.g., aqueous solutions, and in vivo either enterally, parenterally,advantageously intravenously, e.g., as a suspension or in aqueoussolution. The dosage in vitro may range between about 10⁻³ molar and10⁻⁹ molar concentrations. A therapeutically effective amount in vivomay range depending on the route of administration, between about0.1-500 mg/kg, or between about 1-100 mg/kg.

The activity of a compound according to the present invention can beassessed by the in vitro & in vivo methods provided infra.

The compound of the present invention may be administered eithersimultaneously with, or before or after, one or more other therapeuticagent. The compound of the present invention may be administeredseparately, by the same or different route of administration, ortogether in the same pharmaceutical composition as the other agents.

In one embodiment, the invention provides a product comprising acompound of formula (I) and at least one other therapeutic agent as acombined preparation for simultaneous, separate or sequential use intherapy. In one embodiment, the therapy is the treatment of a viralinfection or disease associated with viral infection or conditionmediated by hepatitis C virus. Products provided as a combinedpreparation include a composition comprising the compound of formula (I)and the other therapeutic agent(s) together in the same pharmaceuticalcomposition, or the compound of formula (I) and the other therapeuticagent(s) in separate form, e.g. in the form of a kit.

In one embodiment, the invention provides a pharmaceutical compositioncomprising a compound of formula (I) and another therapeutic agent(s).Optionally, the pharmaceutical composition may comprise apharmaceutically acceptable excipient, as described above.

In one embodiment, the invention provides a kit comprising two or moreseparate pharmaceutical compositions, at least one of which contains acompound of formula (I). In one embodiment, the kit comprises means forseparately retaining said compositions, such as a container, dividedbottle, or divided foil packet. An example of such a kit is a blisterpack, as typically used for the packaging of tablets, capsules and thelike.

The kit of the invention may be used for administering different dosageforms, for example, oral and parenteral, for administering the separatecompositions at different dosage intervals, or for titrating theseparate compositions against one another. To assist compliance, the kitof the invention typically comprises directions for administration.

In the combination therapies of the invention, the compound of theinvention and the other therapeutic agent may be manufactured and/orformulated by the same or different manufacturers. Moreover, thecompound of the invention and the other therapeutic may be broughttogether into a combination therapy: (i) prior to release of thecombination product to physicians (e.g. in the case of a kit comprisingthe compound of the invention and the other therapeutic agent); (ii) bythe physician themselves (or under the guidance of the physician)shortly before administration; (iii) in the patient themselves, e.g.during sequential administration of the compound of the invention andthe other therapeutic agent.

Accordingly, the invention provides the use of a compound of formula (I)for treating a disease or condition caused by or associated with HCVinfection, wherein the medicament is prepared for administration withanother therapeutic agent. The invention also provides the use ofanother therapeutic agent for treating a disease or condition caused byor associated with HCV infection, wherein the medicament is administeredwith a compound of formula (I).

The invention also provides a compound of formula (I) for use in amethod of treating a disease or condition caused by or associated withHCV infection, wherein the compound of formula (I) is prepared foradministration with another therapeutic agent. The invention alsoprovides another therapeutic agent for use in a method of treating adisease or condition caused by or associated with HCV infection, whereinthe other therapeutic agent is prepared for administration with acompound of formula (I). The invention also provides a compound offormula (I) for use in a method of treating a disease or conditioncaused by or associated with HCV infection, wherein the compound offormula (I) is administered with another therapeutic agent. Theinvention also provides another therapeutic agent for use in a method oftreating a disease or condition caused by or associated with HCVinfection, wherein the other therapeutic agent is administered with acompound of formula (I).

The invention also provides the use of a compound of formula (I) fortreating a disease or condition caused by or associated with HCVinfection, wherein the patient has previously (e.g. within 24 hours)been treated with another therapeutic agent. The invention also providesthe use of another therapeutic agent for treating a disease or conditioncaused by or associated with HCV infection, wherein the patient haspreviously (e.g. within 24 hours) been treated with a compound offormula (I).

In one embodiment, the other therapeutic agent is selected from secondtherapeutic agents which are active against viruses and, in particular,against HCV. The compound and agent may be administered in a single orseparate formulations. Agents active against HCV include, but are notlimited to, interferon-α, pegylated interferon-α (peginterferon-α),albinterferon-α2b (alblFN, Novartis/Human Genome Science),PEG-Interferon lambda (BMS/ZymoGenetics), ribavirin, levovirin,viramidine, a combination of interferon-α and ribavirin, a combinationof peginterferon-α and ribavirin, a combination of alblFN and ribavirin,a combination of interferon-α and levovirin, a combination ofpeginterferon-α and levovirin, and a combination of alblFN andlevovirin. Interferon-α includes, but is not limited to, recombinantinterferon-α2a (such as ROFERON interferon available fromHoffman-LaRoche, Nutley, N.J.), interferon-α2b (such as Intron-Ainterferon available from Schering Corp., Kenilworth, N.J., USA), aconsensus interferon, and a purified interferon-α product. Pegylatedinterferon-α includes, but is not limited to, PEG IFN-α2a (such asPegsys available from Hoffman-LaRoche, Nutley, N.J.), PEG IFN-α2b (suchas Peglntron available from Schering Corp., Kenilworth, N.J., USA), Fora discussion of ribavirin and its activity against HCV, see J. O.Saunders and S. A. Raybuck, “Inosine Monophosphate Dehydrogenase:Consideration of Structure, Kinetics and Therapeutic Potential,” Ann.Rep. Med. Chem., 35:201-210 (2000).

The agents active against hepatitis C virus also include agents thatinhibit HCV NS2 or NS3 proteases, HCV NS5B polymerase, HCV NS5A protein,HCV NS3 helicase, HCV NS4B protein, HCV p7 protein, HCV NS4A protein,HCV IRES and protein translation, HCV entry, HCV assembly, HCV egress,and inosine 5′-monophosphate dehydrogenase, cyclophilins or other hostfactors that are required for HCV replication. Still other compoundsinclude those disclosed in WO 2004/014313 and WO 2004/014852 and in thereferences cited therein.

Specific antiviral agents include BI-201335 (Boehringer Ingelheim),telaprevir (Vertex), VX-813 (Vertex), VX-500 (Vertex), boceprevir(Schering-Plough), Sch 900518 (Schering-Plough), ITMN-191/R7227(Intermune/Roche), ITMN-5489 (Intermune), MK-7009 (Merck), TMC435(Tibotec), BMS-650032 (Bristol-Myers-Squibb), PHX1766 (Phenomix),GS-9256 (Gilead), VCH-916 (Vertex), VCH-759 (Vertex), VCH-222/VX-222(Vertex), ABT-333 (Abbott), ANA-598 (Anadys), PF-868,554 (Pfizer),MK-3281 (Merck), PSI-7851 (Pharmasset), R7128 (Pharmasset/Roche), R1626(Roche), GS9190 (Gilead), B1-207127 (Boehringer Ingelheim), JTK-652(Japan Tobacco Inc.), IDX375 (Idenix), Valopicitabine/NM283 (Idenix),IDX-184 (Idenix), AZD2836/A-831 (Arrow/AstraZeneca), AZD7295/A-689(Arrow/AstraZeneca), BMS-790052 (Bristol-Myers-Squibb), PPI-461(Presidio), EDP-239 (Enanta), Ceplene (Maxim Pharmaceuticals), Civacir(Nabi Biopharmaceuticals Inc, VX-497 (Vertex Pharmaceuticals Inc.),XTL-002 (XTL Biopharmaceuticals), isatoribine and its prodrugsANA971,ANA975 and ANA773 (Anadys), NIM811 (Novartis), DEBIO-025(DebioPharm/Novartis), SCY-635 (Scynexis), and nitazoxanide (Romark),IDN-6556 (Idun Pharmaceuticals), IP-501 (Indevus Pharmaceuticals), ISIS14803 (ISIS Pharmaceuticals Inc.),

In some embodiments, the compositions and methods of the presentinvention contain a compound of the invention and interferon. In someaspects, the interferon is selected from the group consisting ofinterferon alpha 2B, pegylated interferon alpha, consensus interferon,interferon alpha 2A, and lymphoblastoid interferon tau.

In other embodiments the compositions and methods of the presentinvention contain a compound of the invention and a compound havinganti-HCV activity is selected from the group consisting of interleukin2, interleukin 6, interleukin 12, a compound that enhances thedevelopment of a type 1 helper T cell response, interfering RNA,anti-sense RNA, Imiquimod, ribavirin, an inosine 5′-monophospatedehydrogenase inhibitor, amantadine, and rimantadine.

In still other embodiments, the compound having anti-HCV activity isRibavirin, levovirin, viramidine, thymosin alpha-1, an inhibitor of NS3serine protease, and inhibitor of inosine monophosphate dehydrogenase,interferon-alpha, or pegylated interferon-alpha alone or in combinationwith Ribavirin or viramidine.

In another embodiments, the compound having anti-HCV activity is saidagent active against HCV is interferon-alpha or pegylatedinterferon-alpha alone or in combination with Ribavirin or viramidine.

General Synthetic Methods

The compounds disclosed herein can be prepared by following the generalprocedures and examples set forth below. It will be appreciated thatwhere typical or preferred process conditions (i.e., reactiontemperatures, times, mole ratios of reactants, solvents, pressures,etc.) are given, other process conditions can also be used unlessotherwise stated. Optimum reaction conditions may vary with theparticular reactants or solvent used, but such conditions can bedetermined by one skilled in the art by routine optimization procedures.

Additionally, as will be apparent to those skilled in the art,conventional protecting groups may be necessary to prevent certainfunctional groups from undergoing undesired reactions. Suitableprotecting groups for various functional groups as well as suitableconditions for protecting and deprotecting particular functional groupsare well known in the art. For example, numerous protecting groups aredescribed in T. W. Greene and P. G. M. Wuts, Protecting Groups inOrganic Synthesis, Third Edition, Wiley, New York, 1999, and referencescited therein.

If the compounds of this invention contain one or more chiral centers,such compounds can be prepared or isolated as pure stereoisomers, i.e.,as individual enantiomers or diastereomers, or as stereoisomer-enrichedmixtures. All such stereoisomers (and enriched mixtures) are includedwithin the scope of this invention, unless otherwise indicated. Purestereoisomers (or enriched mixtures) may be prepared using, for example,optically active starting materials or stereoselective reagentswell-known in the art. Alternatively, racemic mixtures of such compoundscan be separated using, for example, chiral column chromatography,chiral resolving agents and the like.

Typically, the compounds of formula (I) can be prepared according to theSchemes provided infra

General Procedures

EXAMPLE A

Compound according to general structure A-3 could be synthesized bycoupling reaction between fragment A-1 and fragment A-2 with CuI andtrans-cyclohexane diamine as promoters followed by hydrolysis of themethyl ester under basic condition.

EXAMPLE B

Compound according to general structure B-3 could be synthesized byfollowing method (Scheme II). B-1 could be converted to B-2 byhydrolyzing the methyl ester under basic condition followed by cleavingBoc with HCl. B-2 could react with sulfonyl chloride to give sulfonamideB-3. Or B-2 could undergo reductive amination with aldehyde to giveamine B-4.

EXAMPLE C

Compounds according to general structure C-3 and C-5 could besynthesized by followed method. Amine C-1 could be converted to pyridylsulfonamide C-2 by reacting with pyridine sulfonyl chloride.Displacement of chloride with amine would provide C-3. C-1 could reactwith 4-fluro phenylsulfonyl chloride to give C-4. Displacement offluoride with amine would give C-5.

The invention further includes any variant of the present processes, inwhich an intermediate product obtainable at any stage thereof is used asstarting material and the remaining steps are carried out, or in whichthe starting materials are formed in situ under the reaction conditions,or in which the reaction components are used in the form of their saltsor optically pure antipodes.

Compounds of the invention and intermediates can also be converted intoeach other according to methods generally known to those skilled in theart.

Within the scope of this text, only a readily removable group that isnot a constituent of the particular desired end product of the compoundsof the present invention is designated a “protecting group”, unless thecontext indicates otherwise. The protection of functional groups by suchprotecting groups, the protecting groups themselves, and their cleavagereactions are described for example in standard reference works, such asJ. F. W. McOmie, “Protective Groups in Organic Chemistry”, Plenum Press,London and New York 1973, in T. W. Greene and P. G. M. Wuts, “ProtectiveGroups in Organic Synthesis”, Third edition, Wiley, New York 1999, in“The Peptides”; Volume 3 (editors: E. Gross and J. Meienhofer), AcademicPress, London and New York 1981, in “Methoden der organischen Chemie”(Methods of Organic Chemistry), Houben Weyl, 4th edition, Volume 15/I,Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jeschkeit,“Aminosauren, Peptide, Proteine” (Amino acids, Peptides, Proteins),Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and in JochenLehmann, “Chemie der Kohlenhydrate: Monosaccharide and Derivate”(Chemistry of Carbohydrates: Monosaccharides and Derivatives), GeorgThieme Verlag, Stuttgart 1974. A characteristic of protecting groups isthat they can be removed readily (i.e. without the occurrence ofundesired secondary reactions) for example by solvolysis, reduction,photolysis or alternatively under physiological conditions (e.g. byenzymatic cleavage).

Salts of compounds of the present invention having at least onesalt-forming group may be prepared in a manner known to those skilled inthe art. For example, salts of compounds of the present invention havingacid groups may be formed, for example, by treating the compounds withmetal compounds, such as alkali metal salts of suitable organiccarboxylic acids, e.g. the sodium salt of 2-ethylhexanoic acid, withorganic alkali metal or alkaline earth metal compounds, such as thecorresponding hydroxides, carbonates or hydrogen carbonates, such assodium or potassium hydroxide, carbonate or hydrogen carbonate, withcorresponding calcium compounds or with ammonia or a suitable organicamine, stoichiometric amounts or only a small excess of the salt-formingagent preferably being used. Acid addition salts of compounds of thepresent invention are obtained in customary manner, e.g. by treating thecompounds with an acid or a suitable anion exchange reagent. Internalsalts of compounds of the present invention containing acid and basicsalt-forming groups, e.g. a free carboxy group and a free amino group,may be formed, e.g. by the neutralisation of salts, such as acidaddition salts, to the isoelectric point, e.g. with weak bases, or bytreatment with ion exchangers.

Salts can be converted into the free compounds in accordance withmethods known to those skilled in the art. Metal and ammonium salts canbe converted, for example, by treatment with suitable acids, and acidaddition salts, for example, by treatment with a suitable basic agent.

Mixtures of isomers obtainable according to the invention can beseparated in a manner known to those skilled in the art into theindividual isomers; diastereoisomers can be separated, for example, bypartitioning between polyphasic solvent mixtures, recrystallisationand/or chromatographic separation, for example over silica gel or bye.g. medium pressure liquid chromatography over a reversed phase column,and racemates can be separated, for example, by the formation of saltswith optically pure salt-forming reagents and separation of the mixtureof diastereoisomers so obtainable, for example by means of fractionalcrystallisation, or by chromatography over optically active columnmaterials.

Intermediates and final products can be worked up and/or purifiedaccording to standard methods, e.g. using chromatographic methods,distribution methods, (re-) crystallization, and the like.

The following applies in general to all processes mentioned hereinbefore and hereinafter.

All the above-mentioned process steps can be carried out under reactionconditions that are known to those skilled in the art, including thosementioned specifically, in the absence or, customarily, in the presenceof solvents or diluents, including, for example, solvents or diluentsthat are inert towards the reagents used and dissolve them, in theabsence or presence of catalysts, condensation or neutralizing agents,for example ion exchangers, such as cation exchangers, e.g. in theH+form, depending on the nature of the reaction and/or of the reactantsat reduced, normal or elevated temperature, for example in a temperaturerange of from about −100° C. to about 190° C., including, for example,from approximately −80° C. to approximately 150° C., for example at from−80 to −60° C., at room temperature, at from −20 to 40° C. or at refluxtemperature, under atmospheric pressure or in a closed vessel, whereappropriate under pressure, and/or in an inert atmosphere, for exampleunder an argon or nitrogen atmosphere.

At all stages of the reactions, mixtures of isomers that are formed canbe separated into the individual isomers, for example diastereoisomersor enantiomers, or into any desired mixtures of isomers, for exampleracemates or mixtures of diastereoisomers, for example analogously tothe methods described under “Additional process steps”.

The solvents from which those solvents that are suitable for anyparticular reaction may be selected include those mentioned specificallyor, for example, water, esters, such as lower alkyl-lower alkanoates,for example ethyl acetate, ethers, such as aliphatic ethers, for examplediethyl ether, or cyclic ethers, for example tetrahydrofuran or dioxane,liquid aromatic hydrocarbons, such as benzene or toluene, alcohols, suchas methanol, ethanol or 1- or 2-propanol, nitriles, such asacetonitrile, halogenated hydrocarbons, such as methylene chloride orchloroform, acid amides, such as dimethylformamide or dimethylacetamide, bases, such as heterocyclic nitrogen bases, for examplepyridine or N-methylpyrrolidin-2-one, carboxylic acid anhydrides, suchas lower alkanoic acid anhydrides, for example acetic anhydride, cyclic,linear or branched hydrocarbons, such as cyclohexane, hexane orisopentane, methycyclohexane, or mixtures of those solvents, for exampleaqueous solutions, unless otherwise indicated in the description of theprocesses. Such solvent mixtures may also be used in working up, forexample by chromatography or partitioning.

The compounds, including their salts, may also be obtained in the formof hydrates, or their crystals may, for example, include the solventused for crystallization. Different crystalline forms may be present.

The invention relates also to those forms of the process in which acompound obtainable as an intermediate at any stage of the process isused as starting material and the remaining process steps are carriedout, or in which a starting material is formed under the reactionconditions or is used in the form of a derivative, for example in aprotected form or in the form of a salt, or a compound obtainable by theprocess according to the invention is produced under the processconditions and processed further in situ.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents and catalysts utilized to synthesize thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4^(th) Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21).

In one embodiment, the invention provides a method of modulating viralactivity in a subject, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound according tothe definition of formula (I). Methods of inhibiting viral replicationor inhibiting viral load in a subject are provided, wherein the virus isa member of the Flaviviridae family of viruses such as hepatitis Cvirus.

In one embodiment, the invention provides a method of treating adisorder or a disease in a subject caused by or associated with HCVinfection, wherein the method comprises administering to the subject atherapeutically effective amount of the compound according to thedefinition of formula (I).

In one embodiment, the invention provides a method of treating adisorder or a disease in a subject caused by or associated with HCVinfection, wherein the disorder or the disease is selected from of HCVinfection, liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, liver fibrosis anda suppressed innate intracellular immune response.

In one embodiment, the invention provides a compound according to thedefinition of formula (I), for use as a medicament.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula (I), for the treatment of adisorder or disease in a subject caused by or associated with HCVinfection.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula (I), in the manufacture of amedicament for the treatment of a disorder or disease in a subjectcaused by or associated with HCV infection, wherein said disorder ordisease is in particular selected from HCV infection, liver cirrhosis,chronic liver disease, hepatocellular carcinoma, cryoglobulinaemia,non-Hodgkin's lymphoma, liver fibrosis and a suppressed innateintracellular immune response.

In one embodiment, the invention provides the use of a compoundaccording to the definition of formula (I), for the treatment of adisorder or disease in a subject caused by or associated with HCVinfection, wherein the disorder or disease is selected from HCVinfection, liver cirrhosis, chronic liver disease, hepatocellularcarcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma, liver fibrosis anda suppressed innate intracellular immune response.

In another embodiment, the invention provides compounds according to thedefinition of formula (I), which compounds include the exemplifiedcompounds provided infra. Certain compounds of Formula (I) provided bythe invention include compounds selected from the group consisting of:

-   1.    3-((S)-2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-phenyl-thiophene-2-carboxylic    acid-   2.    3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylic    acid-   3.    3-(3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-phenyl-thiophene-2-carboxylic    acid-   4.    3-[(R)-2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   5.    3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   6.    3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   7.    3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylic    acid-   8.    3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic    acid-   9.    5-(4-Chloro-phenyl)-3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylic    acid-   10.    3-[2-Cyclohexyl-4-(6-dipropylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   11.    3-{(R)-2-Cyclohexyl-4-[6-((R)-2-methyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic    acid-   12.    3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   13.    3-{(R)-2-Cyclohexyl-4-[6-((2S,5R)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic    acid-   14.    3-[2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   15.    3-{(R)-2-Cyclohexyl-4-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylic    acid-   16.    3-[2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   17.    3-[(R)-2-Cyclohexyl-4-(6-diethylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   18.    3-[(R)-2-Cyclohexyl-6-oxo-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   19.    3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   20.    3-[(R)-2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylic    acid-   21.    3-[(R)-2-Cyclohexyl-4-(4-methoxy-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   22.    3-[(R)-2-Cyclohexyl-4-(6-methoxy-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   23.    3-[(R)-2-Cyclohexyl-4-(1-methyl-1H-pyrazole-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   24.    3-{(R)-2-Cyclohexyl-4-[6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-p-tolyl-thiophene-2-carboxylic    acid-   25.    3-(2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   26.    3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   27.    3-((4S,5R)-5-Cyclohexyl-3,4-dimethyl-2-oxo-imidazolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   28.    5-(4-Chloro-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-thiophene-2-carboxylic    acid-   29.    3-[(R)-5-Cyclohexyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   30.    3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   31.    3-[(R)-5-Cyclohexyl-2-(3-methanesulfonyl-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   32.    3-{(R)-5-Cyclohexyl-2-[(2-methoxy-ethylamino)-methyl]-3-oxo-morpholin-4-yl}-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   33.    3-(4-Cyclohexyl-2-oxo-[1,3]oxazinan-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   34.    3-((R)-5-Cyclohexyl-2-morpholin-4-ylmethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   35.    3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   36.    3-((2S,5R)-2-Cyanomethyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   37.    3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   38.    3-((R)-5-Cyclohexyl-2,2-dimethyl-3-oxo-morpholin-4-yl)-5-p-tolyl-thiophene-2-carboxylic    acid-   39.    3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic    acid-   40.    3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   41.    3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   42.    3-[(2S,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   43.    3-[(2R,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   44.    3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   45.    3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   46.    3-(6-Cyclohexyl-3-hydroxy-3-methyl-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylic    acid-   47.    3-((R)-3-Cyclohexyl-5-oxo-1,9-dioxa-4-aza-spiro[5.5]undec-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   48.    3-[6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   49.    3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   50.    3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   51.    3-((R)-5-Cyclohexyl-2-hydroxymethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   52.    3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   53.    3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   54.    3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   55.    3-[6-Cyclohexyl-3-hydroxy-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   56.    3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   57.    3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   58.    3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   59.    3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   60.    3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   61.    3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   62.    3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   63.    3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   64.    3-[(S)-6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   65.    3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid-   66.    3-[(S)-6-Cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic    acid

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees centrigrade. If not mentioned otherwise, all evaporations areperformed under reduced pressure, typically between about 15 mm Hg and100 mm Hg (=20-133 mbar). The structure of final products, intermediatesand starting materials is confirmed by standard analytical methods,e.g., microanalysis and spectroscopic characteristics, e.g., MS, IR,NMR. Abbreviations used are those conventional in the art.

All starting materials, building blocks, reagents, acids, bases,dehydrating agents, solvents, and catalysts utilized to synthesis thecompounds of the present invention are either commercially available orcan be produced by organic synthesis methods known to one of ordinaryskill in the art (Houben-Weyl 4th Ed. 1952, Methods of OrganicSynthesis, Thieme, Volume 21). Further, the compounds of the presentinvention can be produced by organic synthesis methods known to one ofordinary skill in the art as shown in the following examples.

LIST OF ABBREVIATIONS

-   Ac acetyl-   ACN Acetonitrile-   AcOEt/EtOAc Ethyl acetate-   AcOH acetic acid-   aq aqueous-   Ar aryl-   Bn benzyl-   Bu butyl (nBu=n-butyl, tBu=tert-butyl)-   CDI Carbonyldiimidazole-   CH₃CN Acetonitrile-   DBU 1,8-Diazabicyclo[5.4.0]-undec-7-ene-   DCE 1,2-Dichloroethane-   DCM Dichloromethane-   DIPEA N-Ethyldiisopropylamine-   DMAP Dimethylaminopyridine-   DMF N,N′-Dimethylformamide-   DMSO Dimethylsulfoxide-   EI Electrospray ionisation-   Et₂O Diethylether-   Et₃N Triethylamine-   Ether Diethylether-   EtOH Ethanol-   FC Flash Chromatography-   h hour(s)-   HATU O-(7-Azabenzotriazole-1-yl)-N,N,N′N′-tetramethyluronium    hexafluorophosphate-   HBTU O-(Benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium    hexafluorophosphate-   HCl Hydrochloric acid-   HOBt 1-Hydroxybenzotriazole-   HPLC High Performance Liquid Chromatography-   H₂O Water-   L liter(s)-   LC-MS Liquid Chromatography Mass Spectrometry-   Me methyl-   MeI Iodomethane-   MeOH Methanol-   mg milligram-   min minute(s)-   mL milliliter-   MS Mass Spectrometry-   Pd/C palladium on charcoal-   PG protecting group-   Ph phenyl-   Prep Preparative-   Rf ratio of fronts-   RP reverse phase-   Rt Retention time-   rt Room temperature-   SiO₂ Silica gel-   TBAF Tetrabutylammonium fluoride-   TEA Triethylamine-   TFA Trifluoroacetic acid-   THF Tetrahydrofurane-   TLC Thin Layer Chromatography    HPLC Methods:    -   A. 4.6 mm×150 mm C18 reverse phase column, 5.0 um particle size        running a gradient of 5-95% MeCN/water (0.1% formic acid) over a        period of 20 min at a flow rate of 1.5 mL/min at 30° C. DAD-UV        detection, 220-600 nm    -   B. 3 mm×100 mm C18 reverse phase column, 3.0 um particle size        running a gradient of 5-95% MeCN/water (0.1% formic acid) over a        period of 7.45 min at a flow rate of 1 mL/min at 40° C. DAD-UV        detection, 220-600 nm.    -   C. 4.6 mm×50 mm C18 reverse phase column, 5.0 um particle size        running a gradient of 5-95% MeCN/water (0.1% formic acid) over a        period of 3.4 min at a flow rate of 2 mL/min at 40° C. DAD-UV        detection, 220-600 nm.    -   D. 4.6 mm×50 mm C18 reverse phase column, 5.0 um particle size        running a gradient of 5-95% MeCN/water (0.1% ammonium formate)        over a period of 3.4 min at a flow rate of 2 mL/min at 40° C.        DAD-UV detection, 220-600 nm.    -   E. 3.0 mm×33 mm C8 reverse phase column, 3.0 um particle size        running a gradient of 5-95% MeCN/water (0.1% ammonium formate)        over a period of 2.0 min at a flow rate of 2 mL/min at 50° C.        DAD-UV detection, 220-600 nm.        Procedures

EXAMPLE 1 Synthesis of3-[2-Cyclohexyl-4-(2-fluoro-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid [Compound 40]

Step 1. Synthesis of[(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzylester

To a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (25g, 88 mmol) in DMF (100 mL) at −10° C. was added HATU (36.7 g, 96 mmol,1.0 equiv) followed by N,O-dimethyl hydroxyamine HCl salt (10.3 g, 105mmol, 1.2 equiv). To this solution was then slowly added N-methylmorpholine (28.9 mL, 263 mmol, 3.0 equiv). The internal temperature wascarefully monitored. During the addition, the internal temperature roseto 0° C. The solution was stirred at 0° C. for 2 hours after which thesolution was diluted with EtOAc (500 mL) and washed with sat. aq. NaHCO₃solution, water, 1.0 N aq. HCl solution and brine. The organic layer wasdried over Na₂SO₄ and the solvent including DMF was removed undervacuum. The residue was diluted with EtOAc and the solution was washedwith water, brine, dried (MgSO₄) and concentrated to give product[(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzylester 26 g (yield 90%).

Step 2. Synthesis of ((R)-1-Cyclohexyl-2-oxo-ethyl)-carbamic acid benzylester

To a solution of[(R)-Cyclohexyl-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid benzylester (27 g, 82 mmol) in THF (400 mL) at −20° C. was slowly added LiAlH₄(4.06 g, 106 mmol, 1.3 equiv). LiAlH₄ was freshly ground from pelletpurchased from Aldrich. During addition, the internal temperature wascarefully monitored and did not rise above 0° C. After addition themixture was stirred at 0° C. and the reaction was monitored by TLC andLCMS. After 1 hour, the reaction solution was cooled at −10° C. andquenched by slow addition of sat. aq. KHSO₄ solution until pH=5. Themixture was partitioned between water and EtOAc. The phases wereseparated and the organic layer was concentrated. The residue wasdissolved in EtOAc and the solution was washed with water, brine, driedover Na₂SO₄ and concentrated to give product((R)-1-Cyclohexyl-2-oxo-ethyl)-carbamic acid benzyl ester 22 g (99%).The material was continued to next step with no further purification.

Step 3. Synthesis of((R)-2-Benzyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acidmethyl ester

A solution of aldehyde (25 g, 91 mmol) in CH₂Cl₂ (350 mL) at 0° C. wasadded methyl glycine hydrochloride salt (22.8 g, 182 mmol, 2.0 equiv)followed by DIPEA (23.8 mL, 136 mmol, 1.5 equiv). To the solution wasthen added sodium triacetoxyborohydride (28.9 g, 136 mmol, 1.5 equiv).The mixture was stirred at room temperature for 3 hours. The reactionwas quenched by addition of sat. aq. NaHCO₃ solution until pH=8. Thephases were separated and the aqueous layer was extracted with CH₂Cl₂.The combined organic layer was washed with water, brine, dried (MgSO₄)and concentrated to give product((R)-2-Benzyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acidmethyl ester (34 g, 107% yield). The crude product which containedimpurity and solvent was continued to the next step with no furtherpurification.

Step 4. Synthesis of (R)-6-Cyclohexyl-piperazin-2-one

To a 2.0 L round bottom flask containing a solution of((R)-2-Benzyloxycarbonylamino-2-cyclohexyl-ethylamino)-acetic acidmethyl ester (27 g, 77 mmol) in MeOH (300 mL) under a stream of N₂ wasadded Pd (10% on carbon, 4.1 g, 0.05 equiv). The mixture was stirredunder 1.0 atm of H₂ for 18 hours. The mixture was diluted with 100 mL ofCH₂Cl₂ and filtered through Celite. The filtrate was concentrated togive crude product (R)-6-Cyclohexyl-piperazin-2-one 18 g (127%). Theproduct, which contained impurity and solvent, was continued to the nextstep with no further purification.

Step 5. Synthesis of (R)-3-Cyclohexyl-5-oxo-piperazine-1-carboxylic acidtert-butyl ester

To a solution of (R)-6-Cyclohexyl-piperazin-2-one (7.3 g, 40 mmol) inCH₂Cl₂ (200 mL) was added (Boc)₂O (10.5 g, 11.1 mmol, 1.2 equiv). Thesolution was stirred at room temperature for 1 hour, after which thesolvent was removed under vacuum. The residue was purified by silica gelcolumn chromatography (acetone/heptane, 40%). The collected fraction wasconcentrated until ˜100 mL solvent left. The solid was filtered anddried to give product (R)-3-Cyclohexyl-5-oxo-piperazine-1-carboxylicacid tert-butyl ester 6.7 g (59%). The ee of product was determined tobe >98% by chiral SFC.

Step 6. Synthesis of 3-bromo-5-phenyl-thiophene-2-carboxylic acid methylester

To a 250 round bottom flask equipped with refluxing condenser was addedCuBr₂ (11.5 g, 51 mmol, 1.2 equiv), CH₃CN (250 mL) and t-butyl nitrite(6.63 g, 64.3 mmol, 1.5 equiv). The solution was heated at 65° C. and tothis solution was added a solution of3-amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (10.0 g, 42.0mmol) in CH₃CN (50 mL). The resulting mixture was heated at 65° C. for 1hour. The reaction mixture was then cooled at room temperature and addedto 1.0 N HCl aq. solution. EtOAc was added and the phases wereseparated. The aqueous layer was extracted with EtOAc. The organic layerwas washed with water, brine, dried (Na₂SO₄) and concentrated. Theresidue was purified by silica gel to give product3-bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester 7.5 g.

Step 7. Synthesis of(R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yI)-5-oxo-piperazine-1-carboxylicacid tert-butyl ester

A tube was charged with trans-cyclohexanediamine (162 mg, 1.42 mmol, 0.5equiv), K₂CO₃ (783 mg, 5.67 mmol, 2.0 equiv),3-bromo-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.01 g, 3.40mmol, 1.2 equiv), CuI (270 mg, 1.42 mmol, 0.5 equiv),(R)-3-Cyclohexyl-5-oxo-piperazine-1-carboxylic acid tert-butyl ester(800 mg, 2.83 mmol, 1.0 equiv) and 1,4-dioxane (3.0 mL). The tube wasthen flushed with N₂ and sealed. The reaction mixtures were heated at110° C. for 72 hours after which it was diluted with EtOAc and filtered.The filtrate was washed with 1.0 N HCl aq. solution, brine, dried(Na₂SO₄) and concentrated. The residue was purified by silica gel columnchromatography (EtOAc/heptane, 50%) to give product(R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-5-oxo-piperazine-1-carboxylicacid tert-butyl ester 415 mg.

Step 8. Synthesis of3-((R)-2-Cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid

To a solution of(R)-3-Cyclohexyl-4-(2-methoxycarbonyl-5-phenyl-thiophen-3-yl)-5-oxo-piperazine-1-carboxylicacid tert-butyl ester (1.8 g, 3.6 mmol) in THF/water/MeOH (1/1/1, 30 mL)was added lithium hydroxide monohydrate (0.45 g, 10.8 mmol, 3.0 equiv)and the resulting solution was heated at 55° C. for 1 hour. The reactionwas quenched by addition of 1.0 N HCl aq. solution until pH=5. Thesolution was then extracted with EtOAc. The organic layer was washedwith brine, dried (Na₂SO₄) and concentrated to give(R)-4-(2-Carboxy-5-phenyl-thiophen-3-yl)-3-cyclohexyl-5-oxo-piperazine-1-carboxylicacid tert-butyl ester3-((R)-2-Cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid (1.7 g, 97%). The material was continued to the next step with nofurther purification.

To a solution of(R)-4-(2-Carboxy-5-phenyl-thiophen-3-yl)-3-cyclohexyl-5-oxo-piperazine-1-carboxylicacid tert-butyl ester (1.7 g) in 1,4-dioxane (5.0 mL) was added asolution of 4.0 N HCl in dioxane (20 mL) and the resulting mixture wasstirred at room temperature of 2 hours. The solvent was then removedunder vacuum to give product as HCl salt (1.4 g, 95%).

Step 9. Synthesis of racemic3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid

To a solution of (R)-benzyloxycarbonylamino-cyclohexyl-acetic acid (15g, 51.5 mmol) in CH₂Cl₂ (60 mL) at 0° C. was added N-methylmorpholine(12.5 mL, 113 mmol, 2.2 equiv) and at −25° C. isobutyl chloroformate(6.76 mL, 51.5 mmol, 1.0 equiv) was added. The resulting solution wasstirred at −10° C. for 1 hour, after which to this solution was added asuspension N,O-dimethyl hydroxyamine HCl salt (5.52 g, 56.5 mmol, 1.1equiv) in CH₂Cl₂ (60 mL). The mixture was then stirred at roomtemperature for 3 hours, after which the solution was diluted with EtOAc(500 mL) and washed with 1.0 N aq. HCl solution and brine. The organiclayer was dried over Na₂SO₄ and concentrated. Racemic3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid was synthesized from this material following step 2-8 describedabove.

Step 10. Synthesis of3-[2-Cyclohexyl-4-(2-fluoro-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid

To a solution of3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid (15.0 mg, 0.036 mmol, 1.0 equiv) in MeCN (0.2 mL) at roomtemperature, was added NaOH (0.40 mL, 1.5 N solution, 0.60 mmol, 16.7equiv) and 2-fluoro-benzenesulfonyl chloride (11.4 mg, 0.059 mmol, 1.64equiv). The mixture was stirred at room temperature for 30 minutes. Themixture was acidified with 3 N HCl (0.3 mL), and then diluted with EtOAc(10 mL). The mixture was washed with water (5 mL), brine (5 mL), thendried (over Na₂SO₄), filtered and the filtrate was concentrated underreduced pressure. The residue was purified by HPLC (0.1% NH₄OH) to giveproduct (5.0 mg, 24%) as white solid. MS: 543 [M−H⁺]. ¹H-NMR (400MH_(Z), CDCl₃): δ 1.12 (m, 3H), 1.34 (m, 1H), 1.45-1.90 (m, 7H),2.70-2.87 (m, 2H), 3.34 (d, 1H), 3.60-3.70 (m, 2H), 3.95 (d, 1H), 4.18(d, 1H), 7.13 (s, 1H), 7.21 (t, 1H), 7.27 (t, 1H), 7.30-7.40 (m, 3H),7.51-7.61 (m, 3H), 7.83 (t, 1H).

EXAMPLE 2 Synthesis of3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid [Compound 135] Step 1. Synthesis of3-[(R)-4-(6-Chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid

To a solution of3-(2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid (0.80 g, 1.90 mmol, 1.0 equiv) in MeCN (20 mL) at room temperature,was added 6-chloro-pyridine-3-sulfonyl chloride (1.10 g, 5.20 mmol, 2.7equiv) and followed by NaOH (6.94 mL, 1.5 N solution, 10.4 mmol, 5.5equiv) dropwise. The mixture was stirred at room temperature for 10minutes. The mixture was acidified with 3 N HCl (2.5 mL), and thendiluted with EtOAc (50 mL). The mixture was washed water (25 mL), brine(25 mL), dried (over Na₂SO₄), filtered and concentrated to give crudeproduct (1.0 g, 94%) as yellow-green solid. MS: 560 [M−H⁺].

Step 2. Synthesis of3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid

To a solution of3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid (100 mg, 0.18 mmol, 1.0 equiv) in DMF (0.8 mL) at room temperaturewas added pyrrolidine (127 mg, 1.79 mmol, 10.0 equiv) and Et₃N (0.37 mL,2.68 mmol, 15.0 equiv). The mixture was stirred at 70° C. for 2 hours.The mixture was then cooled to room temperature and filtered. Thefiltrate was concentrated and purified by HPLC (0.1% NH₄OH) to giveproduct (35 mg, 33%) as white solid. MS: 595 [M−H⁺]. ¹H-NMR (400 MH_(Z),MeOD): δ 1.10-1.23 (m, 5H), 1.40-2.00 (m, 10H), 3.04-3.12 (m, 2H), 3.20(t, 2H), 3.42 (d, 2H), 3.88 (d, 1H), 3.97 (br, 1H), 4.07 (d, 1H), 6.62(s, 1H), 7.19 (s, 1H), 7.32 (t, 1H), 7.40 (t, 2H), 7.63 (d, 2H), 7.83(m, 1H), 8.44 (d, 1H).

EXAMPLE 3 Synthesis of3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 236]

Step 1. Synthesis of (R)-5-Cyclohexyl-morpholin-3-one

To a solution containing 3.8 g (26.5 mmol, 1.0 equiv) of(R)-2-amino-2-cyclohexyl-ethanol in 100 mL of THF was added sodiumhydride (1.4 g, 58.4 mmol, 60% in mineral oil, 2.2 equiv). The reactionmixture was stirred at 25° C. for 30 minutes, at which time hydrogenevolution had ceased. The mixture was cooled at 0° C. and was addedethyl chloroacetate (3.3 g, 26.5 mmol, 1.0 equiv), dropwise, over 5minutes. The reaction mixture was stirred for 1 hour at 25° C. and then2 hours at reflux. The solvent was removed under vacuum and to theresidue was added 1.0 N HCl aq. solution until pH=6. The mixture wasextracted with ethyl acetate. The resulting organic extracts were washedwith brine, dried over sodium sulfate and concentrated in vacuo. Theresidue was recrystallized from EtOAc/heptane to give product 2.8 g. Themother liquid was concentrated and the residue was purified by silicagel column chromatography (acetone/heptane 50%) to give product 1.3 g.Combined yield 4.1 g (84%)

Step 2. Synthesis of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

A 350 mL heavy wall round bottom flask was charged with TEA (33.7 mL, 24mmol, 5.0 equiv), BINAP (3.0 g, 4.83 mmol, 0.1 equiv),5-bromo-thiophene-2-carboxylic acid (48.3 mmol, 1.0 equiv), CuI (0.184g, 0.97 mmol, 0.02 equiv), Pd₂dba₃ (2.2 g, 2.4 mmol, 0.05 equiv) and DMF(40.0 mL). The flask was flushed with N₂ and to the mixture was addedt-butyl acetylene (15.8 g, 193 mmol, 4.0 equiv). The mixture was sealedand stirred at 70° C. for 48 hours. After cooled at room temperature,the reaction mixture was filtered and the filtrate was concentratedunder vacuum. The residue was acidified with 3.0 N HCl until pH=4. Theaqueous layer was extracted with EtOAc. The organic layer was washedwith brine, dried over Na₂SO₄ and concentrated. The residue was purifiedby silical gel, EtOAc/heptane 5% to EtOAc/heptane 30% with 2% of AcOH togive product 6.5 g (yield 65%).

Step 3. Synthesis of3-Bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid

To a of solution of 5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid (6.5 g, 31.3 mmol, 1.0 equiv) in THF (150 mL) at −78° C. was addedn-BuLi (44.9 mL, 1.6 M in heptane, 71.9 mmol, 2.3 equiv) and theresulting solution was stirred at −78° C. for 1 hour. To the solutionwas then added 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (16.2 g, 62.5mmol, 2.0 equiv) and the solution was allowed to warm to roomtemperature over 2 hours. The reaction was quenched by addition of sat.aq. NH₄Cl solution and the mixture was extracted with EtOAc. The organiclayers were combined, washed with brine, dried over Na₂SO₄ andconcentrated. The crude material was continued to the next step with nofurther purification.

Step 4. Synthesis of3-Bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methylester

The product from previous step was dissolved in DMF (15.0 mL) and to thesolution was added K₂CO₃ (8.6 g, 62.6 mmol, 2.0 equiv) and MeI (8.9 g,62.6 mmol, 2.0 equiv). The resulting mixture was stirred at roomtemperature for 18 hours. The mixture was filtered and the filtrate wasconcentrated under vacuum. The residue was purified by silica gel columnchromatography, heptane/EtOAc 15% to give product 7.0 g (74% yield for 2steps).

Step 5. Synthesis of3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

A heavy wall flask was charged with trans-cyclohexane diamine (623 mg,5.5 mmol, 0.5 equiv),3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methylester (4.27 g, 14.2 mmol, 1.3 equiv), K₂CO₃ (3.02 g, 21.8 mmol, 2.0equiv), CuI (1.04 g, 5.5 mmol, 0.5 equiv), 5-cyclohexyl-morpholin-3-one(2.0 g, 10.9 mmol, 1.0 equiv) and 1,4-dioxane (10.0 mL). The mixture wasflushed with N₂ and stirred at 110° C. for 48 hours. The mixture wasfiltered through celite and the filtrate was concentrated under vacuum.The residue was purified by silica gel, EtOAc/heptane 50% to giveproduct 2.8 g (yield 50%).

Step 6. Synthesis of3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (35 mg, 0.087 mmol, 1.0 equiv) in THF (0.5mL), MeOH (0.5 mL), water (0.5 mL) was added lithium hydroxidemonohydrate (10.9 mg, 0.26 mmol, 3.0 equiv). The resulting mixture wasstirred at 50° C. for 1 hour, after which the reaction was neutralizedby addition of 1.0 N HCl aq. solution to pH=6. The mixture was extractedwith EtOAc. The organic layers were combined, washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by reverse phaseHPLC to give product 18 mg (yield 53%). MS: 390.1 [M+H⁺]. ¹H-NMR (400MHz, CD₃OD): 6.87 (s, 1H), 4.19 (s, 2H), 4.05 (m, 2H), 3.82 (s, 1H),1.43-1.90 (m, 6H), 1.06-1.39 (m, 14H)

EXAMPLE 4 Synthesis of3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 299]

Step 1. Synthesis of cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one

To a solution of 5-Cyclohexyl-morpholin-3-one (1.0 g, 5.5 mmol, 1.0equiv) in DMF (15.0 mL) at 0° C. was added NaH (0.26 g, 60% in oil, 6.5mmol, 1.2 equiv) slowly. The mixture was stirred at room temperature for30 minutes, then it was added PMBCI (0.94 g, 6.0 mmol, 1.1 equiv). Afterstirred at room temperature for 2 hours, the reaction mixture wasquenched by added to sat. aq. NH₄Cl solution. The mixtures wereextracted with EtOAc. The organic layers were combined and washed withbrine, dried over MgSO₄ and concentrated. The residue was purified bysilica gel, acetone/heptane 30% to give 1.5 g (91%) of5-Cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one.

Step 2. Synthesis of2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one

To a solution of 5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one (700mg, 2.3 mmol, 1.0 equiv) in THF (10.0 mL) at −78° C. was added n-BuLi(1.58 mL, 1.6 M in heptane, 2.54 mmol, 1.1 equiv). The resultingsolution was stirred at −78° C. for 30 minutes, after which it was addeda solution of tert-Butyl-(3-iodo-propoxy)-dimethyl-silane (693 mg, 2.3mmol, 1.0 equiv) in THF (1.0 mL). The solution was stirred at −78° C.for 30 minutes and 2 hours at room temperature after which it wasquenched by addition of sat. aq. NH₄Cl solution. The mixture wasextracted with EtOAc. The organic layer was combined, dried over MgSO₄and concentrated. The residue was purified by silica gel columnchromatography, EtOAc/heptane 30% to give product 480 mg (yield 44%).

Step 3. Synthesis of 5-Cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one

To a solution of2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one(400 mg, 0.84 mmol, 1.0 equiv) in CH₃CN (0.3 mL) and water (0.3 mL) wasadded CAN (922 mg, 1.68 mmol, 2.0 equiv). The mixture was stirred atroom temperature for 1 hour then second portion of CAN (900 mg) wasadded. After stirred at room temperature for 1 hour, the reactionmixture was diluted with EtOAc and the phases were separated. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel column chromatography,EtOAc/heptane 50% to 100% EtOAc to give5-cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one 134 mg.

Step 4. Synthesis of3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

A 10 mL heavy wall vial was charged with trans-cyclohexane diamine (11.8mg, 0.10 mmol, 0.5 equiv),3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methylester (125 mg, 0.41 mmol, 2.0 equiv), K₂CO₃ (57 mg, 0.41 mmol, 2.0equiv), CuI (19.7 mg, 0.10 mmol, 0.5 equiv),5-cyclohexyl-2-(3-hydroxy-propyl)-morpholin-3-one (50 mg, 0.21 mmol, 1.0equiv) and 1,4-dioxane (0.5 mL). The mixture was flushed with N₂ andstirred at 110° C. for 24 hours. The mixture was filtered through celiteand the filtrate was concentrated under vacuum. The residue was purifiedby silica gel, EtOAc/heptane 30% to give product 10 mg (yield 10%). Step5. Synthesis of3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (10 mg, 0.022 mmol, 1.0 equiv) in THF (0.2mL), MeOH (0.2 mL), water (0.2 mL) was added lithium hydroxide hydrate(4.5 mg, 0.11 mmol, 5.0 equiv). The resulting mixture was stirred at 50°C. for 30 minutes, after which the reaction was neutralized by additionof 1.0 N HCl aq. solution to pH=6. The mixture was extracted with EtOAc.The organic layers were combined, washed with brine, dried over Na₂SO₄and concentrated. The residue was purified by reverse phase HPLC to giveproduct 2.6 mg. MS: 448.5 [M+H⁺]

EXAMPLE 5 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 311]

Step 1.(R)-2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-one

To a solution of diisopropyl amine (138 mg, 1.36 mmol, 1.3 equiv) in THF(6.0 mL) at −78° C. was added n-BuLi (0.79 mL, 1.6 mL in heptane, 1.26mmol, 1.2 equiv) and the resulting solution was stirred at −78° C. for10 minutes. To the solution was added a solution of2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-morpholin-3-one(500 mg, 1.05 mmol, 1.0 equiv) in THF (2 mL) and the solution wasstirred at −78° C. for 30 mins. MeI was added and the solution wasstirred at −78° C. for 1 hour then slowly warmed to room temperatureover 2 hours. The reaction was quenched by addition of sat. aq. NH₄Clsolution. The mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, EtOAc/heptane 20% to giveproduct(S)-2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-one110 mg and product(R)-2-[3-(tert-butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-one205 mg.

Step 2. Synthesis of(R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-morpholin-3-one

To a solution of TBS ether (200 mg, 0.41 mmol, 1.0 equiv) in CH₃CN (1.0mL) and water (1.0 mL) was added CAN (461 mg, 0.82 mmol, 2.0 equiv). Themixture was stirred at room temperature for 1 hour then second portionof CAN (400 mg) was added. After stirred at room temperature for 1 hour,the reaction mixture was diluted with EtOAc and the phases wereseparated. The organic layer was washed with brine and dried over Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography, EtOAc/heptane 50% to 100% EtOAc to give product 45 mg(43% yield).

Step 3. Synthesis of3-[(R2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a 10 mL vial was added trans-cyclohexane diamine (13.4 mg, 0.12 mmol,1.0 equiv), 3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (70.8 mg, 0.24 mmol, 2.0 equiv), K₂CO₃ (32.5 mg, 0.24mmol, 2.0 equiv), CuI (22 mg, 0.12 mmol, 1.0 equiv),(R)-5-cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-morpholin-3-one (30 mg,0.12 mmol, 1.0 equiv) and 1,4-dioxane (0.4 mL). The mixture was flushedwith N₂ and stirred at 120° C. for 18 hours. The mixture was filteredthrough celite and the filtrate was concentrated under vacuum. Theresidue was purified by silica gel column chromatography, EtOAc/heptane80% to give product 15 mg (yield 26%).

Step 4. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (15 mg, 0.032 mmol, 1.0 equiv) in THF (0.5mL), MeOH (0.5 mL), water (0.5 mL) was added lithium hydroxide (3.8 mg,0.16 mmol, 5.0 equiv). The resulting mixture was stirred at 50° C. for30 minutes, after which the reaction was neutralized by addition of 1.0N HCl aq. solution to pH=6. The mixture was extracted with EtOAc. Theorganic layers were combined, washed with brine, dried over Na₂SO₄ andconcentrated. The residue was purified by reverse phase HPLC to giveproduct 4.3 mg (yield 29%). MW: 462.2 [M+H]. ¹H-NMR (400 MHz, MeOD): δ6.91 (s, 1H), 4.23 (d, 1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H),1.96-1.52 (m, 10H), 1.45 (s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m,1H).

EXAMPLE 6 Synthesis of3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 7]

(S)-2-[3-(tert-Butyl-dimethyl-silanyloxy)-propyl]-5-cyclohexyl-4-(4-methoxy-benzyl)-2-methyl-morpholin-3-onefrom Example 5 step 1 was carried on according to procedure in Example 5step 2-step 4 to provide3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid. MS: 462.2[M+H⁺]. ¹H-NMR (400 MHz, CD₃OD): δ 6.93 (s, 1H), 4.12 (d,1H), 3.91 (d, 1H), 3.66 (s, 1H), 3.54 (t, 2H), 2.14 (m, 1H), 1.91 (m,1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H), 1.06-1.37 (m, 14H).

EXAMPLE 7 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 330]

Step 1. Synthesis of3-((R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (600 mg, 1.49 mmol, 1.0 equiv) in THF (5.0 mL) at −78°C. was added LDA (0.82 mL, 2.0 M in THF, 1.64 mmol, 1.1 equiv) and theresulting solution was stirred at −78° C. for 20 minutes. To thesolution was then added allyliodide (300 mg, 1.78 mmol, 1.2 equiv). Thesolution was warmed to room temperature and stirred at this temperaturefor 30 minutes. The reaction was quenched by addition of sat. aq. NH₄Clsolution. The mixture was extracted with EtOAc. The organic layer waswashed with brine, dried over Na₂SO₄ and concentrated. The residue waspurified by silica gel column chromatography, EtOAc/heptane 25% to give3-((2S,5R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl 140 mg,3-((2R,5R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester 60 mg and mixed fraction 200 mg.

Step 2. Synthesis of3-((2S,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester and product3-((2R,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (120 mg, 0.27 mmol, 1.0 equiv) in THF (1.0 mL) at −78°C. was added LDA (0.16 mL, 2.0 M in THF, 0.32 mmol, 1.2 equiv) and theresulting solution was stirred at −78° C. for 20 minutes. To thesolution was then added methyliodide (192 mg, 1.35 mmol, 5.0 equiv). Thesolution was warmed to room temperature and the stirred at thistemperature for 30 minutes. The reaction was quenched by addition ofsat. aq. NH₄Cl solution. The mixture was extracted with EtOAc. Theorganic layer was washed with brine, dried over Na₂SO₄ and concentrated.The residue was purified by silica gel column chromatography,EtOAc/heptane 25% to give product3-((2S,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester 18 mg and product3-((2R,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester 50 mg.

Step 3. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((2R,5R)-2-Allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (0.40 g, 0.87 mmol, 1.0 equiv) in acetone (6.0 mL) wassequentially added N-methylmorpholine oxide (0.31 g, 2.63 mmol, 3.0equiv), water (2.0 mL) and OsO₄ (0.44 g, 0.044 mmol, 0.05 equiv, 2.5 wt% in t-butanol) at 0° C. The mixture was stirred at room temperature for60 minutes, after which the reaction was quenched by adding brinesolution (0.5 mL) and EtOAc (10 mL). The organic layer was separated,dried (over Na₂SO₄) and concentrated. The crude material was continuedto the next step with no further purification.

Step 4. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester from the previous step was dissolved in 4.0 ml of THFand 0.3 mL of solution was taken out for the reaction. To the stirredsolution was added THF (0.3 mL), MeOH (0.3 mL), water (0.3 mL), andLiOH.H₂O (25.6 mg, 0.61 mmol, 10.0 equiv) and the resulting solution wasstirred at room temperature for 30 minutes. The reaction was quenched byaddition of 3.0 N HCl aqueous solution until pH=5. To the solution wasthen added EtOAc and the phases were separated. The aqueous layer wasextracted by EtOAc. The organic layers were combined, dried (overNa₂SO₄) and concentrated. The residue was purified by HPLC (0.1% NH₄OH,MeCN/H₂O, 10%-90%) to give product (11 mg, 37.7% yield) as white solid.MS: 478 [M−H⁺].

EXAMPLE 8 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 323]

Step 1. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester from Example 7 Step 3 was dissolved in 4 ml THF, and3.7 mL solution was taken out for the reaction. To the stirred solutionwas added THF (2.3 mL), water (2.0 mL), and then sodium periodate (0.28g, 1.31 mmol, 1.6 equiv) at 0° C. The resulting solution was stirred atroom temperature for 30 minutes. And then at 0° C. another portion ofsodium periodate (0.09 g, 0.44 mmol, 0.5 equiv) was added to the mixtureand stirred for another 30 minutes at room temperature. The reaction wasquenched by adding brine solution (0.5 mL) and EtOAc (10 mL). Theorganic layer was separated, dried (over Na₂SO₄) and concentrated. Theresidue was dissolved in ethanol (6.0 mL) and to the resulting solutionat 0° C. was added sodium borohydride (0.27 g, 7.0 mmol, 8.8 equiv). Themixture was stirred at 0° C. for 15 minutes after which the reaction wasquenched by adding water (2.0 mL) and EtOAc (10 mL). The organic layerwas separated, dried (over Na₂SO₄) and concentrated to give product 128mg (yield 35%). The crude product was continued to the next step with nofurther purification. MS: 462 [M−H⁺].

Step 2. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (128 mg, 0.28 mmol, 1.0 equiv) in THF (2.0mL), MeOH (1.0 mL) and water (1.0 mL) was added LiOH.H₂O (93 mg, 2.22mmol, 8.0 equiv) and the resulting solution was stirred at roomtemperature for 30 minutes. The reaction was quenched by addition of 3.0N HCl aqueous solution until pH=5. To the solution was then added EtOAcand the phases were separated. The aqueous layer was extracted by EtOAc.The organic layers were combined and dried (over Na₂SO₄) and thenconcentrated. The residue was purified by HPLC (0.1% NH₄OH, MeCN/H₂O,10%-90%) to give product (87 mg, 78.2% yield) as white solid. MS: 448.3[M+H⁺]. ¹H-NMR (400 MHz, CD₃OD): 6.87 (s, 1H), 4.24 (tert, 1H), 3.93 (d,1H), 3.62-3.82 (m, 3H), 2.08-2.21 (m, 1H), 1.88-2.04 (m, 2H), 1.56-1.87(m, 4H), 1.43-1.56 (m, 4H), 0.98-1.35 (m, 14H)

EXAMPLE 9 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 8] Step 1. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((2R,5R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (0.20 g, 0.45 mmol, 1.0 equiv) in acetone (3.0 mL) wassequentially added N-methylmorpholine oxide (0.160 g, 1.35 mmol, 3.0equiv), water (1.0 mL) and OsO₄ (0.22 g, 0.023 mmol, 0.05 equiv, 2.5 wt% in t-butanol) at 0° C. The mixture was stirred at room temperature for60 minutes, after which the reaction was quenched by adding brinesolution and EtOAc. The organic layer was separated, dried (over Na₂SO₄)and concentrated. The crude material was continued to the next step withno further purification.

The crude material from previous step was dissolved in 3.0 ml THF andwater (1.0 mL) and to the solution was added sodium periodate (0.19 g,0.92 mmol, 2.0 equiv) at 0° C. The resulting solution was stirred atroom temperature for 30 minutes after which brine solution and EtOAc wasadded. The organic layer was separated, dried (over Na₂SO₄) andconcentrated. The residue was dissolved in ethanol (3.0 mL) and to theresulting solution at 0° C. was added sodium borohydride (0.136 g, 3.6mmol, 8.0 equiv). The mixture was stirred at 0° C. for 15 minutes afterwhich the reaction was quenched by adding water (2.0 mL) and EtOAc (10mL). The organic layer was separated, dried (over Na₂SO₄) andconcentrated to give product 45 mg (yield 22%). The crude product wascontinued to the next step with no further purification.

Step 2. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (45 mg, 0.10 mmol, 1.0 equiv) in THF (2.0mL), MeOH (1.0 mL) and water (1.0 mL) was added LiOH.H₂O (33 mg, 0.8mmol, 8.0 equiv) and the resulting solution was stirred at roomtemperature for 30 minutes. The reaction was quenched by addition of 3.0N HCl aqueous solution until pH=5. To the solution was then added EtOAcand the phases were separated. The aqueous layer was extracted by EtOAc.The organic layers were combined and dried (over Na₂SO₄) and thenconcentrated. The residue was purified by reverse phase HPLC to giveproduct (25 mg, 57% yield) as white solid.

MS: 434.2 [M+H⁺]. ¹H-NMR (400 MHz, CD₃OD): δ 6.90 (s, 1H), 4.24 (tert,1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d, 1H), 3.71 (d, 1H), 3.66 (t,1H), 2.21 (m, 1H), 1.41-1.98 (m, 8H), 1.05-1.37 (m, 15H).

EXAMPLE 10 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 311]

To a solution of3-((2R,5R)-2-allyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (50 mg, 0.11 mmol, 1.0 equiv) in THF (1.0 mL) wasadded 9-BBN (0.5 M solution in THF, 0.55 ml, 0.27 mmol, 2.5 equiv) at 0°C. The reaction mixture was then stirred at room temperature for 2hours. To the solution was then cooled in an ice water bath and wasadded EtOH, followed by aq. NaOH solution and H₂O₂ aq. solution. Duringaddition the reaction internal temperature was kept between 5° C. and10° C. The reaction mixture was then heated to reflux for 90 minutes.After cooled at room temperature, the reaction mixture was extractedwith EtOAc. The organic layer was dried over Na₂SO₄ and concentrated invacuo. The residue was purified by prep-HPLC to give the product 26 mg.MW: 462.2 [M+H]⁺. ¹H-NMR (400 MHz, MeOD): δ 6.91 (s, 1H), 4.23 (d, 1H),3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45 (s,3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H).

EXAMPLE 11 Synthesis of3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 35]

Step 1. Synthesis of(S)-5-Cyclohexyl-5-((S)-1-phenyl-ethylamino)-pentanoic acid ethyl ester

A solution of TiCl₄ in DCM (8.8 mL, 1.0 M solution in DCM, 8.8 mmol, 0.5equiv) was added dropwisely to a vigorously stirred ice cooled solutionof s-methyl benzyl amine (2.78 g, 23.0 mmol, 1.3 equiv) and TEA (10.7 g,106 mmol, 6.0 equiv) in DCM (50 mL). The solution was heated to refluxand 5-Cyclohexyl-5-oxo-pentanoic acid ethyl ester (4.0 g, 17.6 mmol, 1.0equiv) was added over 1 minute. The solution was then heated at refluxfor 2 hours, after which, it was cooled to room temperature and dilutedwith ether, filtered through Celite. The cloudy solution was washed withsat. aq. NaHCO₃, brine, dried over MgSO₄ and concentrated. The residuewas dissolved in EtOH (40.0 mL) and at −78° C. was added NaBH₄. Afterstirred at 30 minutes, the reaction mixture was warmed to 0° C. andstirred at 0° C. for 30 minutes. To the solution was then added 6.0 Naq. HCl solution until pH=3. The organic solvent was removed undervacuum and the residue was basified with sat. aq. NaHCO₃ until pH=9. Themixture was extracted with EtOAc and the organic layer was washed withbrine, dried over Na₂SO₄ and concentrated. The residue was purified bysilica gel, EtOAc/heptane 0-15% to give product 2.3 g (yield 39%) as themajor product which eluted from the column first.

Step 2. Synthesis of (S)-6-Cyclohexyl-piperidin-2-one

To a solution of (S)-5-Cyclohexyl-5-((S)-1-phenyl-ethylamino)-pentanoicacid ethyl ester (2.0 g, 6.0 mmol, 1.0 equiv) in MeOH (60 mL) was addedPd (1.6 g, 10% on carbon, 1.51 mmol, 0.25 equiv) and ammonium formate(3.8 g, 60.3 mmol, 10.0 equiv). The mixture was heated to reflux for 2hours. The solution was then cooled at room temperature and filteredthrough Celite. The filtrate was concentrated and the residue waspurified by silica gel column chromatography, acetone/heptane 50% togive product 1.05 g (96% yield).

Step 3. Synthesis of3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a 10 mL vial was added trans-cyclohexane diamine (283 mg, 2.5 mmol,0.5 equiv), 3-Bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (2.24 g, 7.4 mmol, 1.5 equiv), K₂CO₃ (1.37 g, 9.9mmol, 2.0 equiv), CuI (473 mg, 2.5 mmol, 0.5 equiv),(S)-6-Cyclohexyl-piperidin-2-one (900 mg, 5.0 mmol, 1.0 equiv) and1,4-dioxane (5.0 mL). The mixture was flushed with N₂ and stirred at110° C. for 48 hours. The mixture was filtered through Celite and thefiltrate was concentrated under vacuum. The residue was purified bysilica gel column chromatography, EtOAc/heptane 30% to give product 800mg (yield 40%).

Step 4. Synthesis of3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (10 mg, 0.025 mmol, 1.0 equiv) in THF (0.3mL), MeOH (0.3 mL), water (0.3 mL) was added lithium hydroxidemonohydrate (5.2 mg, 0.12 mmol, 5.0 equiv). The resulting mixture wasstirred at 50° C. for 1 hour, after which the reaction was neutralizedby addition of 1.0 N HCl aq. solution to pH=6. The mixture was extractedwith EtOAc. The organic layers were combined, washed with brine, driedover Na₂SO₄ and concentrated. The residue was purified by reverse phaseHPLC to give product 6.0 mg (yield 62%). MW: 388.4 [M+H]⁺. ¹H-NMR (400MHz, MeOD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25 (m, 1H), 1.88-1.38 (m,6H), 1.29 (s, 9H), 1.18 (m, 4H), 1.06 (m, 4H).

EXAMPLE 12 Synthesis of3-((S)-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid: [Compound 322] Step 1. Synthesis of3-((3S,6S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (3.2 g, 7.97 mmol, 1.0 equiv) in THF (15.0 ml) wasadded NaHMDS (1.0 M in THF) at −78° C. and the resulting solution wasstirred at −78° C. for 1.5 hours. To this solution was then added asolution of (S)-(+)-(camphorsulfonyl)oxaziridine (3.65 g, 15.94 mmol,2.0 equiv) in THF (10 ml) and the reaction mixture was stirred at −78°C. for 3 hours. The reaction was quenched by addition of sat. NH₄Cl aq.solution. The mixture was extracted with EtOAc and the combined organiclayer was dried over Na₂SO₄, and concentrate. The residue was purifiedby silica gel column chromatography, (Et₂O/DCM 5%˜40%) to give 1.5 g ofthe desired product (yield 45%). MS: 418 [M+H⁺]

Step 2. Synthesis of5-(3,3-Dimethyl-but-1-ynyl)-3-[(3S,6S)-6-(1-ethyl-pentyl)-3-hydroxy-2-oxo-piperidin-1-yl]-thiophene-2-carboxylicacid

To a solution of3-((3S,6S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (1.5 g, 3.59 mmol, 1 equiv.) in THF/H₂O/MeOH (5.0mL/5.0 mL/1.0 mL) was added LiOH.H₂O (0.79 g, 17.56 mmol, 5.0 equiv.) atroom temperature. The reaction mixture was stirred at 50° C. for 20minutes. The reaction was then acidified to pH=5 by addition of 3.0 NHCl aq. solution and the mixture was extracted with EtOAc. The organiclayer was dried over Na₂SO₄, and concentrated. The residue was purifiedby prep-HPLC(XBridge Prep C 18 5 um, 30×50 mm) in basic condition (0.1%NH₄OH, 10%˜45% CH₃CN/H₂O, 10 min run, 40 ml/min) to give 850 mg ofproduct (yield 57%). MS: 404 [M+H⁺]. ¹H-NMR (400 MHz, MeOD): δ 6.95 (s,1H), 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m, 1H), 1.94-1.67 (m, 8H), 1.38(m, 1H), 1.33 (s, 9H), 1.17 (m, 5H).

EXAMPLE 13 Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylicacid [Compound 70]

Step 1. Synthesis of3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-thiophene-2-carboxylic acidmethyl ester

A flask was charged with 3-amino-thiophene-2-carboxylic acid methylester (600 mg, 3.82 mmol, 1.0 equiv), 5-cyclohexyl-5-oxo-pentanoic acidethyl ester (864 mg, 3.82 mmol, 1.0 equiv), phenyl silane (496 mg, 4.58mmol, 1.2 equiv), dibutyltin dichloride (116 mg, 0.38 mmol, 0.1 equiv)and dioxane (3.0 mL). The resulting solution was heated at 60° C. for 18hours. The solution was then concentrated and the residue was purifiedby silica gel column chromatography, CH₂Cl₂/heptane 30% to 100%, to give3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-thiophene-2-carboxylic acidmethyl ester 810 mg (yield 57%).

Step 2. Synthesis of3-(4-Carboxy-1-cyclohexyl-butylamino)-thiophene-2-carboxylic acid methylester

To a solution of methyl ester (300 mg, 0.82 mmol, 1.0 equiv) in THF (1.0mL), MeOH (1.0 mL), water (1.0 mL) was added lithium hydroxide (58.6 mg,2.45 mmol, 3.0 equiv). The resulting mixture was stirred at roomtemperature for 4 hours, after which the organic solvent was removedunder vacuum. The resulted solution was neutralized by addition of 1.0 NHCl aq. solution until pH=6. The mixture was extracted with EtOAc. Theorganic layers were combined, dried over Na₂SO₄ and concentrated to givedesired carboxylic acid.

Step 3. Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylic acid methylester

To a solution of carboxylic acid (700 mg, 2.06 mmol, 1.0 equiv) intoluene (30.0 mL) was added pyridine (816 mg, 10.3 mmol, 5.0 equiv) at0° C. followed by thionyl chloride (245 mg, 2.06 mmol, 1.0 equiv). Thesolution was stirred at 0° C. for 1 hour. The reaction was quenched byaddition of sat. aq. NH₄Cl solution. The mixture was extracted withEtOAc. The organic layers were combined, washed with brine, dried overNa₂SO₄ and concentrated. The residue was purified by silica gel,heptane/EtOAc 1/1 to give product 350 mg (yield 53%).

Step 4. Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylicacid methyl ester

A 5 mL vial was charged with3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylic acid methylester (32 mg, 0.10 mmol, 1.0 equiv), 1-bromo-4-fluoro benzene (17 mg,0.10 mmol, 1.0 equiv), potassium carbonate (20.6 mg, 0.15 mmol, 1.5equiv), tricyclophenylphosphine tetrafluroborate (8.7 mg, 0.024 mmol,0.24 equiv), Pd(OAc)₂ (2.7 mg, 0.012 mmol, 0.12 equiv), pivalic acid(6.1 mg, 0.060 mmol, 0.6 equiv) and DMA (0.3 mL). The resulted mixturewas flushed with nitrogen and stirred at 100° C. for 18 hours. Themixture was loaded to silica gel column and flushed with EtOAc/heptane67% to give product 27 mg (yield 65%).

Step 5. Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (20 mg, 0.048 mmol, 1.0 equiv) in THF (0.5mL), EtOH (0.2 mL), water (0.5 mL) was added lithium hydroxidemonohydrate (19 mg, 0.48 mmol, 10.0 equiv). The resulting mixture wasstirred at 55° C. for 3 hours, after which the mixture was concentratedunder vacuum. The residue was purified by reverse phase HPLC to giveproduct 15.0 mg (yield 78%).

EXAMPLE 14 Synthesis of3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 181]

Step 1. Synthesis of (R)-4-Cyclohexyl-oxazolidin-2-one

To a solution of (R)-2-Amino-2-cyclohexyl-ethanol.HCl salt (1.0 g, 5.57mmol, 1.0 equiv) in CH₂Cl₂ (30.0 mL) at 0° C. was added DIPEA (1.94 mL,11.1 mmol, 2.0 equiv) followed by triphosgene (4.95 g, 16.7 mmol, 3.0equiv) and the resulting solution was stirred at room temperature for 12hours. The solution was then concentrated and the residue was dilutedwith EtOAc. The solution was washed with water, brine, dried over Na₂SO₄and concentrated. The residue was purified by silica gel columnchromatography, (EtOAc 100%) to give product 520 mg.

Step 2. Synthesis of3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

A heavy wall flask was charged with trans-cyclohexane diamine (18.9 mg,0.17 mmol, 0.5 equiv),3-bromo-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylic acid methylester (100 mg, 0.332 mmol, 1.0 equiv), K₂CO₃ (92 mg, 0.664 mmol, 2.0equiv), CuI (31.6 mg, 0.166 mmol, 0.5 equiv),(R)-4-cyclohexyl-oxazolidin-2-one (56.2 mg, 0.332 mmol, 1.0 equiv) and1,4-dioxane (0.5 mL). The mixture was flushed with N₂ and stirred at110° C. for 18 hours, after which the mixture was filtered throughcelite and the filtrate was concentrated under vacuum. The residue waspurified by silica gel, EtOAc/heptane 30% to give product 54 mg (yield42%).

Step 3. Synthesis of3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of methyl ester (50 mg, 0.128 mmol, 1.0 equiv) in THF (0.5mL), MeOH (0.5 mL), water (0.5 mL) was added lithium hydroxidemonohydrate (16.2 mg, 0.38 mmol, 3.0 equiv). The resulting mixture wasstirred at 50° C. for 1 hour, after which the reaction was neutralizedby addition of 1.0 N HCl aq. solution to pH=6. The mixture purifieddirectly by reverse phase HPLC to give product 28 mg (yield 58%). MS:376.4 [M+H⁺].

EXAMPLE 15 Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid [Compound 4]

Step 1. Synthesis of3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester

A flask was charged with 3-amino-5-phenyl-thiophene-2-carboxylic acidmethyl ester (515 mg, 2.2 mmol, 1.0 equiv), 5-cyclohexyl-5-oxo-pentanoicacid ethyl ester (500 mg, 2.2 mmol, 1.0 equiv), phenyl silane (240 mg,2.2 mmol, 1.0 equiv), dibutyltin dichloride (67 mg, 0.22 mmol, 0.1equiv) and dioxane (2.0 mL). The resulting solution was heated at 120°C. with microwave for 2 hours. The solution was then concentrated andthe residue was purified by silica gel column chromatography,EtOAc/heptane 5% to 40%, to give oil that contained starting material.The material was further purified with silica gel column chromotography,EtOH/DCM 2% to 10% to give product 150 mg (yield 15%).

Step 2. Synthesis of3-(4-Carboxy-1-cyclohexyl-butylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of3-(1-Cyclohexyl-4-ethoxycarbonyl-butylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester (40 mg, 0.09 mmol, 1.0 equiv) in THF (0.4 mL), EtOH(0.2 mL), water (0.4 mL) was added lithium hydroxide (18.9 mg, 0.45mmol, 5.0 equiv). The resulting mixture was stirred at 50° C. for 2hours, after which the organic solvent was removed under vacuum. Theresulted solution was neutralized by addition of 1.0 N HCl aq. solutionuntil pH=6. The mixture was extracted with EtOAc. The organic layerswere combined, dried over Na₂SO₄ and concentrated to product 30 mg(yield 83%).

Step 3. Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a vial containing a solution of3-(4-Carboxy-1-cyclohexyl-butylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester (40 mg, 0.096 mmol, 1.0 equiv) in 1,2-dioxane (1.0 mL)was added pyridine (3.8 mg, 0.048 mmol, 0.5 equiv) and Boc₂O (25 mg,0.166 mmol, 1.2 equiv). The vial was then sealed and heated at 65° C.for 18 hours. The solution was concentrated and the residue was purifiedby silica gel column chromatography, EtOAc/Heptane 5% to 100% to giveproduct 15 mg (yield 39%).

Step 4. Synthesis of3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid

To a solution of methyl ester (15 mg, 0.038 mmol, 1.0 equiv) in THF (0.2mL), EtOH (0.2 mL), water (0.1 mL) was added lithium hydroxidemonohydrate (7.9 mg, 0.19 mmol, 5.0 equiv). The resulting mixture wasstirred at 50° C. for 2 hours, after which the mixture was concentratedunder vacuum. The residue was purified by reverse phase HPLC to giveproduct 5.0 mg (yield 35%). MW: 384.1 [M+H]⁺. ¹H-NMR (400 MHz, CDCl₃): δ7.43 (m, 2H), 7.21 (m, 3H), 6.94 (m, 1H), 3.68 (m, 1H), 2.45 (m, 2H),2.21 (m, 1H), 1.83-1.51 (m, 12H), 1.32 (m, 2H).

EXAMPLE 16 Synthesis of3-(2-Cyclohexyl-4-hydroxy-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester [Compound 12] Step 1.3-(1-Cyclohexyl-2-ethoxycarbonyl-ethylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of 3-Cyclohexyl-3-oxo-propionic acid ethyl ester (1.0 g,5.0 mmol, 1.0 equiv) in THF (5.0 mL) was added3-Amino-5-phenyl-thiophene-2-carboxylic acid methyl ester (1.17 g, 5.0mmol, 1.0 equiv) and SnBu₂Cl₂ (0.15 g, 0.50 mmol, 0.1 equiv) at roomtemperature. After stirred at room temperature for 5 minutes, thesolution was added PhSiH₃. The resulting reaction mixture was stirred at65° C. under N₂ for 18 hours, after which the solution was concentratedunder vacuum and the residue was purified by silica gel columnchromatography EtOAc/heptane, 10-60% to give product (0.7 g). MS: 416[M+H⁺].

Step 2.3-(2-Carboxy-1-cyclohexyl-ethylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of3-(1-cyclohexyl-2-ethoxycarbonyl-ethylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester (300 mg, 0.72 mmol, 1.0 equiv) in THF (2.0 mL), EtOH(1.0 mL) and water (2.0 mL) was added LiOH.H₂O (152 mg, 3.6 mmol, 5.0equiv). The mixture was stirred at 55° C. for 20 minutes. The organicsolvent was then evaporated. To the resulting solution was added 3.0 NHCl aq. solution until pH=5-6. The solid was then collected byfiltration and washed with water. The filtrate was extracted with EtOAcand the organic layer was washed with sat. NaHCO₃ aq. solution, brine,dried over Na₂SO₄, and concentrated in vacuo. The crude material wascontinued to the next step with no further purification.

Step 3. Synthesis of3-(2-Cyclohexyl-4,6-dioxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of3-(2-carboxy-1-cyclohexyl-ethylamino)-5-phenyl-thiophene-2-carboxylicacid methyl ester (200 mg, 0.52 mmol, 1.0 equiv) in DCM (1.0 mL) wasadded EDC (148 mg, 0.77 mmol, 1.5 equiv), DMAP (95 mg, 0.77 mmol, 1.5equiv), and Meldrum's acid (75 mg, 0.52 mmol, 1.0 equiv) at 0° C. Themixture was then warmed to room temperature and stirred at thistemperature for 3 hours. To the reaction mixture was then added sat.NaHSO₄ aq. solution. The mixture was extracted with DCM and the organicphase was washed with brine, dried over Na₂SO₄ and concentrated invacuo. The crude material was continued to the next step with no furtherpurification.

The crude product from previous step (240 mg 0.47 mmol, 1.0 equiv) wasdissolved in EtOAc (5.0 mL) and the resulting solution was heated toreflux for 2 hours. To the mixture was then added sat. aq. NaHSO₄solution at room temperature. The mixture was extracted with DCM and theorganic phase was washed with brine, dried over Na₂SO₄ and concentratedin vacuo. The residue was purified by silica gel column chromatography(EtOAc/Heptane 10%˜60%) to give product (160 mg). MS: 412 [M+H⁺]

Step 4. Synthesis of3-(2-Cyclohexyl-4-hydroxy-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a stirred solution of3-(2-Cyclohexyl-4,6-dioxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester (60 mg, 0.15 mmol, 1.0 equiv.) in anhydrous DCM (1.0mL) was added NaBH₄ (11 mg, 0.29 mmol, 2 equiv) and AcOH (0.8 mg, 0.01mmol, 0.1 equiv) at 0° C. The reaction mixture was then stirred at roomtemperature for 4 hours after which the reaction was quenched byaddition of water. The mixture was extracted with DCM. The organic layerwas washed with sat. aq. NaHCO₃ solution, dried over Na₂SO₄ andconcentrated in vacuo. The residue was purified by silica gel columnchromatography (EtOAc/heptane, 10%˜60%) to give product 15 mg. Theproduct was dissolved in THF (0.2 mL), EtOH (0.1 mL) and water (0.2 mL).To the solution was added LiOH.H₂O (7.6 mg, 0.18 mmol, 5 equiv) and theresulting mixture was stirred at 55° C. for 1 hour. The organic solventwas then evaporated and to the resulting solution was added 1.0 N HClaq. solution until pH=4. The solution was extracted with EtOAc, and theorganic layer was washed with sat. NaHCO₃ aqueous solution, brine, driedover Na₂SO₄, and concentrated in vacuo. The residue was purified by HPLCto give product 4 8 mg. MS: 400 [M+H⁺].

EXAMPLE 17 Synthesis of3-(4-Benzoylamino-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid [Compound 21]

Step 1. Synthesis of3-(4-Amino-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of3-(2-cyclohexyl-4,6-dioxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester (400 mg, 0.98 mmol, 1.0 equiv) in MeOH (2.0 mL) wasadded NH₄OAc (375 mg, 4.86 mmol, 5 equiv) and the resulting solution wasstirred at room temperature for 18 hours. The reaction mixture wasconcentrated in vacuo and the residue was dissolved MeOH. To thesolution was added NaCNBH₃ (247 mg, 1.16 mmol, 1.2 equiv) and HOAc (56mg, 0.97 mmol, 1 equiv). The resulting mixture was stirred at roomtemperature for 18 hours. The solvent was then removed in vacuo. To theresidue was added sat. aq. NaHCO₃ solution until pH>8. The mixture wasextracted with DCM. The organic layer was dried over Na₂SO₄ andconcentrated in vacuo. The crude material was continued to the next stepwith no further purification.

Step 2. Synthesis of3-[2-Cyclohexyl-6-oxo-4-(2-phenoxy-acetylamino)-piperidin-1-yl]-5-phenyl-thiophene-2-carboxylicacid methyl ester

To a solution of3-(4-amino-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid methyl ester (30 mg, 0.073 mmol, 1.0 equiv) in DCM (1.0 mL) at 0°C. was added phenoxyacetyl chloride (0.02 ml, 0.145 mmol, 2.0 equiv) andTEA (0.02 mL). The resulting mixture was then stirred at 0° C. for 20minutes after which the solvent was removed under vacuum. The residuewas purified by silica gel column chromatography (EtOAc/hepatane 10%80%) to give product (20 mg). MS: 547 [M+H⁺].)

Step 3. Synthesis of3-[2-Cyclohexyl-6-oxo-4-(2-phenoxy-acetylamino)-piperidin-1-yl]-5-phenyl-thiophene-2-carboxylicacid

To a solution of methyl ester (10 mg, 0.018 mmol, 1.0 equiv) in THF (0.2mL), EtOH (0.1 mL) and water (0.2 mL) was added LiOH.H₂O (8 mg, 0.18mmol, 10 equiv). The mixture was stirred at 55° C. for 30 minutes, afterwhich, the organic solvent was evaporated. To the resulting solution wasadded 3.0 N HCl aq. solution until pH=5. The solution was extracted withEtOAc, and the organic layer was washed with sat. NaHCO₃ aqueoussolution, brine, dried over Na₂SO₄, and concentrated in vacuo. Theresidue was purified by prep-HPLC to give the product 6 mg. MS:533[M+H⁺]. ¹H-NMR (400 MHz, DMSO): δ 10.31 (d, 1H), 7.63 (d, 2H), 7.42(t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98 (m, 3H), 4.61(m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20 (m, 1H),1.88-1.76 (m, 4H), 1.65-1.58 (m, 2H), 1.41-1.05 (m, 6H).

EXAMPLE 18 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid and3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 2] [Compound 3]

To a solution of3-((R)-2-Allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (200 mg, 0.45 mmol, 1.0 equiv) in THF (4.0 mL) at 0°C. was added 9-BBN (2.2 mL, 0.5 M in THF, 1.1 mmol, 2.5 equiv) over 10minutes and the resulting solution was stirred at room temperature for18 hours. The solution was then cooled to 0° C. and to the solution wasadded EtOH, aq. NaOH. solution, aq. H₂O₂ solution. The reaction mixturewas heated to reflux for 90 minutes. After cooled to room temperature,the reaction mixture was extracted with EtOAc. The organic layer wasdried over Na₂SO₄ and the residue was purified by prep-HPLC to giveproduct3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid (20 mg) and3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid (20 mg). The stereochemistry at 2 position of morpholinone has notbeen established. Product 1: MW: 448.3 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD):δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58 (m, 2H),2.02-1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m, 6H). Product 2: MW:448.3 [M+H]⁺. ¹H-NMR (400 MHz, CD₃OD): δ 6.97 (s, 1H), 4.13 (m, 1H),3.90 (m, 1H), 3.82 (m, 1H), 3.57 (m, 2H), 1.97-1.48 (m, 10H), 1.32 (s,9H), 1.26-1.09 (m, 6H).

EXAMPLE 19 Synthesis of3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrimidin-5-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid [Compound 206]

To a solution of3-[(R)-4-(6-chloro-pyridine-3-sulfonyl)-2-cyclohexyl-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid (1.20 g, 2.14 mmol, 1.0 equiv) in acetonitrile (15.0 mL) was addedpotassium phosphate (8.58 ml, 1.0 M aqueous solution, 4.0 equiv) andchloro(2-dicyclohexylphosphino-2′,4′,6′-tri-i-propyl-1,1′-biphenyl)[2-(2-amino ethyl)phenyl]Pd(II) Me-t-butyl ether adduct (0.32 g, 0.43 mmol, 0.2 equiv) at roomtemperature. The mixture was stirred at room temperature for 10 minutesto form a stock solution. To 0.8 mL of above solution was added5-pyrimidinyl boronic acid (17.7 mg, 0.143 mmol, 2.0 equiv) andacetonitrile (0.5 mL) at room temperature. The mixture was stirred at80° C. for 4 hours. The mixture was purified by HPLC (0.1% NH₄OH) toafford the product (15.9 mg, 36.9%). MS: 603.2 [M−H⁺].

EXAMPLE 203-[(R)-2-Cyclohexyl-4-(3-fluoro-2-morpholin-4-yl-benzyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid [Compound 266]

A solution of3-((R)-2-cyclohexyl-6-oxo-piperazin-1-yl)-5-phenyl-thiophene-2-carboxylicacid (50.0 mg, 0.13 mmol, 1.0 equiv) and3-fluoro-2-morpholinobenzaldehyde (108.8 mg, 0.52 mmol, 4.0 equiv) inacetic acid (0.2 mL) and methanol (0.5 mL) was stirred at roomtemperature for 60 minutes. Then sodium triacetoxyborohydride (110.2 mg,0.52 mmol, 4.0 equiv) was added to the mixture and the resulting mixturewas stirred at 75° C. for 3 hours. The solvent was removed by Genevacand the residue was dissolved in EtOAc (6 mL). The organic phase waswashed by brine (3 mL), dried over Na₂SO₄ and concentrated. The residuewas purified by HPLC (0.1% NH₄OH) to afford the product (9 mg, 12%). MS:577.2 [M−H⁺].

EXAMPLE 21 Synthesis of3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 340]

Step 1. Synthesis of3-((S)-3-Bromo-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((3S,6S)-6-cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (200 mg, 0.75 mmol, 1 equiv) in CH₂Cl₂ (1.0 mL) wasadded PBr₃ (1.0 M in CH₂Cl₂, 0.09 ml, 0.38 mmol, 0.8 equiv.) at roomtemperature and the resulting solution was stirred at room temperaturefor 18 hours. The reaction solution was then concentrated under vacuumand the residue was purified by silica gel column chromatography,(EtOAc/Heptane, 10%˜60%) to give product 166 mg (yield 76%). MS: 481[M+H⁺].

Step 2. Synthesis of3-((S)-3-Azido-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To the solution of3-((S)-3-bromo-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (78 mg, 0.16 mmol, 1 equiv.) in DMF (1.0 mL) was addedNaN₃ (12 mg, 0.19 mmol, 1.2 equiv) and the resulting mixture was stirredat 65° C. for 18 hours. The solvent was then removed under vacuum. Theresidue was purified by silica gel column chromatography (EtOAc/Heptane,10%˜60%) to give product 42 mg (yield 56%). MS: 442 [M+H⁺].

Step 3. Synthesis of3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To the solution of3-((S)-3-azido-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (40 mg, 0.09 mmol, 1 equiv) in MeOH (0.5 mL) was addedSnCl₂ (17 mg, 0.09 mmol, 1 equiv) and the resulting solution was stirredat room temperature for 18 hours. The solvent was then removed undervacuum. The residue was dissolved in THF/H₂O/MeOH (0.5 mL/0.5 mL/1.0 mL)and to the solution was added LiOH.H₂O (21 mg, 0.48 mmol, 5 equiv). Thereaction mixture was stirred at 50° C. for 20 minutes. The organicsolvents were removed under vacuum and the residue was acidified to pH=5by addition of 3.0 N HCl aq. solution. The mixture was extracted withEtOAc. The organic layer was dried over Na₂SO₄, and concentrated undervacuum. The residue was purified by prep-HPLC (XBridge Prep C 18 5 um,30×50 mm) in basic condition (0.1% NH₄OH, 10%˜45% CH₃CN/H₂O, 10 min run,40 ml/min) to give product 12 mg. MS: 403 [M+H⁺]. ¹H-NMR (400 MH_(Z),CD₃OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84(m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.31 (s, 9H), 1.16(m, 5H).

EXAMPLE 22 Synthesis of3-((S)-6-cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 341]

Step 1. Synthesis of3-((S)-3-Allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((S)-2-cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (200 mg, 0.5 mmol, 1.0 equiv) in THF (2.0 mL) wasadded LDA (2.0 M in THF, 0.3 mL, 0.6 mmol, 1.2 equiv) at −78° C. and theresulting solution was stirred at −78° C. for 10 minutes. To thesolution was then added 3-iodo-propene (250 mg, 1.5 mmol, 3.0 equiv) andthe reaction mixture was stirred at room temperature for 15 minutes. Thereaction was quenched by addition of water. The mixture was extractedwith EtOAc. The organic layer was washed with sat. NaHCO₃ aq. solutionand brine, dried over Na₂SO₄, and concentrated under vacuum. The residuewas purified by silica gel column chromatography, Heptane/DCM (contained3% EtOAc) to give 60 mg of less polar diastereomer and 100 mg of morepolar diastereomer. MS: 442 [M+H⁺].

Step 2. Synthesis of3-((S)-6-cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (less polar diastereomer from previous step) (60 mg,0.14 mmol, 1.0 equiv) in anhydrous THF (2.0 ml) was added 9-BBN (0.5 Min THF, 0.68 ml, 0.34 mmol, 2.5 equiv) at 0° C. and the resultingsolution was stirred at room temperature for 2 hours. The solution wasthen cooled at 0° C. and to the solution was added EtOH, 1.0 M aq. NaOHsolution and aqueous H₂O₂ solution. The reaction mixture was heated toreflux for 90 minutes and then cooled at room temperature. The mixturewas extracted with EtOAc. The organic layer was dried over Na₂SO₄ andconcentrated under vacuum. The residue was purified by prep-HPLC (0.1%NH₄OH) to give 20 mg of the desired product (yield 33%). MS: 446 [M+H⁺].¹H-NMR (400 MH_(Z), CD₃OD): 6.81 (s, 1H), 4.00 (br, 1H), 3.53 (t, 2H),2.27 (br, 1H), 1.97 (m, 3H), 1.82-1.64 (m, 7H), 1.58 (m, 2H), 1.37 (m,2H), 1.31 (s, 9H), 1.14 (m, 5H).

EXAMPLE 23 Synthesis of3-((S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 343]

Step 1. Synthesis of3-[(S)-6-Cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((S)-3-allyl-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (less polar diastereomer from previous step) (200 mg,0.45 mmol, 1.0 equiv) in acetone (3.0 mL) at 0° C. was addedN-methylmorpholine oxide (160 mg, 1.36 mmol, 3 equiv), water (1.0 mL)and OsO₄ (230 mg, 0.02 mmol, 0.05 equiv). The reaction mixture wasstirred at room temperature for 1 hour. The solution was partitionedbetween brine and EtOAc. The phases were separated and the organic layerwas dried over Na₂SO₄, and concentrated under vacuum. The residue wasdissolved in THF/water (3.0 mL/1.0 mL). To the solution was added NaIO₄(194 mg, 0.9 mmol, 2 equiv), and the resulting mixture was stirred atroom temperature for 30 minutes, after which another portion of NaIO₄(0.5 equiv) was added. After stirred at room temperature for 30 minutes,the mixture was partitioned between brine and EtOAc. The organic layerwas separated, dried over Na₂SO₄, and concentrated. The residue wasdissolved in EtOH (3.0 ml) and the solution was cooled at 0° C. To thesolution was added NaBH₄ and the mixture was stirred at 0° C. for 15minutes. The reaction was quenched by addition of water (2.0 mL) andEtOAc (10.0 mL). The organic layer was separated, dried over Na₂SO₄, andconcentrated. The residue was purified by silica gel columnchromatography, Heptane/EtOAc 1/1 to give 123 mg of the product (yield60%). MS: 446 [M+H⁺]

Step 2. Synthesis of3-((S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of3-[(S)-6-cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (123 mg, 0.28 mmol, 1 equiv.) in THF/H₂O/MeOH (1.0mL/1.0 mL/0.5 mL) was added LiOH.H₂O (60 mg, 1.38 mmol, 5 equiv) and theresulting solution was stirred at 50° C. for 20 minutes. The solutionwas then acidified to pH=5 by addition of 3.0 N HCl aq. solution. Thesolution was extracted with EtOAc. The organic layer was dried overNa₂SO₄, and concentrated. The residue was purified by prep-HPLC(XBridgePrep C 18 5 um, 30×50 mm) in basic condition (0.1% NH₄OH, 10%˜45%CH₃CN/H₂O, 10 min run, 40 ml/min) to give product 28 mg (yield 23%). MS:432 [M+H⁺]. ¹H-NMR (400 MH_(Z), CD₃OD): 6.85 (s, 1H), 3.92 (br, 1H),3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H), 1.97 (m, 2H), 1.78 (m, 7H),1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).

EXAMPLE 24 Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 336]

and3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid [Compound 337]

Step 1. Synthesis of3-[(2R,5R)-5-Cyclohexyl-3-oxo-2-(2-oxo-ethyl)-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-((2R,5R)-2-allyl-5-cyclohexyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (3.15 g, 7.10 mmol, 1.0 equiv) in acetone (40 mL) at0° C. was added N-methylmorpholine oxide (2.51 g, 21.30 mmol, 3.0equiv), water (14 mL) and osmium tetroxide (3.60 g, 2.5% wt in THF, 0.36mmol, 0.05 equiv). The mixture was stirred at room temperature for 60minutes. Acetone was removed under vacuum and the residue waspartitioned between EtOAc (80 mL) and brine (15 mL). The phases wereseparated and the organic layer was dried (over Na₂SO₄) andconcentrated. To the residue was added THF (40 mL) and water (14 mL). At0° C., sodium periodate (2.28 g, 10.65 mmol, 1.5 equiv) was added to themixture and the mixture was stirred at room temperature for 30 minutes.After cooled at 0° C., another portion of sodium periodate (0.76 g, 3.55mmol, 0.5 equiv) was added. The mixture was stirred at room temperaturefor another 30 minutes. Volatile solvent was removed under vacuum andthe residue was partitioned between EtOAc (100 mL) and brine (10 mL).The organic layer was separated, dried (over Na₂SO₄) and concentrated.The residue was purified by silica gel column chromatography(EtOAc/Heptane, 25% to 50%) to give product (2.1 g, 66%). MS: 446.3[M−H⁺].

Step 2. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester and3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester

To a solution of3-[(2R,5R)-5-cyclohexyl-3-oxo-2-(2-oxo-ethyl)-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (1.9 g, 4.26 mmol, 1.0 equiv) in THF (200 mL) at −10°C., was added MeMgBr (1.85 mL, 3.0 M solution in THF, 5.54 mmol, 1.3equiv). The resulting solution was stirred at −10° C. for 20 minutes.The reaction was quenched by addition of 3.0 N HCl aqueous solutionuntil pH=1. The volatile solvent was removed under vacuum and theresidue was partitioned between EtOAc (100 mL) and brine (5 mL). Theseparated organic layer was dried over Na₂SO₄ and concentrated. Theresidue was purified by silica gel column chromatography [Et₂O(2%EtOAc)/Heptane, 25% to 50%] to give3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (0.57 g, 29.0%) and3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (0.80 g, 40.7%). MS: 462.4 [M−H⁺].

Step 3. Synthesis of3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of3-[(2R,5R)-5-cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (650 mg, 1.41 mmol, 1.0 equiv) in THF (10 mL), MeOH (5mL) and water (5 mL) was added LiOH.H₂O (177 mg, 4.22 mmol, 3.0 equiv).The resulting solution was stirred at room temperature for 2 hours. Thevolatile solvent was removed under vacuum and to the residue was addedwater (15 mL). The mixture was cooled to 0° C. and acidified by additionof 3.0 N HCl aqueous solution until pH=1. The precipitate was isolatedby filtration to give product (586 mg, 93%) as white solid. MS: 448.3[M−H⁺]. ¹H NMR (400 MHz, CD₃OD): 1.09-1.31 (m, 8 H) 1.32 (s, 9 H)1.45-1.85 (m, 5 H) 1.89-2.10 (m, 3 H) 3.56-3.61 (m, 1 H) 3.93-4.00 (m, 1H) 4.00-4.10 (m, 1 H) 4.12-4.22 (m, 2H) 6.99 (s, 1 H).

Step 4. Synthesis of3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid

To a solution of3-[(2R,5R)-5-cyclohexyl-2-(2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid methyl ester (420 mg, 0.91 mmol, 1.0 equiv) in THF (8 mL), MeOH (4mL) and water (4 mL) was added LiOH.H₂O (115 mg, 2.73 mmol, 3.0 equiv).The resulting solution was stirred at room temperature for one hour. Thevolatile solvent was removed under vacuum and the residue was acidifiedby addition of 3.0 N HCl aqueous solution until pH=1. The mixture wasextracted with EtOAc (50 mL). The separated organic layer was washedwith brine (10 mL), dried (over Na₂SO₄) and concentrated. The residuewas purified by HPLC (0.1% NH₄OH) to give product (68 mg, 16.7%). MS:448.2 [M−H⁺]. ¹H NMR (400 MHz, CD₃OD) δ 1.07-1.31 (m, 8 H) 1.32 (s, 9 H)1.45-1.60 (m, 2 H) 1.63-1.85 (m, 4 H) 1.87-1.98 (m, 1 H) 2.02-2.11 (m, 1H) 3.60-3.66 (m, 1 H) 3.93-4.03 (m, 2 H) 4.15 (d, 1 H) 4.26-4.35 (m, 1H) 6.94 (s, 1 H).

Additional non-limiting exemplary compounds of the invention areprovided in Table 1. The compounds of Table 1 may be prepared by analogyto the synthetic procedures provided in the general syntheticdescription, the procedures of Examples 1-20 and/or by syntheticmethodology known to the skilled medicinal chemist.

TABLE 1 Compound number Name Structure 1 3-(2-Cyclohexyl-5-oxo-pyrrolidin-1- yl)-5-phenyl- thiophene-2- carboxylic acid

2 3-[(2S,5R)-5- Cyclohexyl-2-(3- hydroxy-propyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

3 3-[(2R,5R)-5- Cyclohexyl-2-(3- hydroxy-propyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

4 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-phenyl- thiophene-2-carboxylic acid

5 3-(6-Cyclohexyl- 3-hydroxy-3- methyl-2-oxo- piperidin-1-yl)-5-p-tolyl-thiophene- 2-carboxylic acid

6 3-((S)-2- Cyclohexyl-5-oxo- pyrrolidin-1-yl)-5- phenyl-thiophene-2-carboxylic acid

7 3-[(2S,5R)-5- Cyclohexyl-2-(3- hydroxy-propyl)-2- methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

8 3-[(2R,5R)-5- Cyclohexyl-2-(2- hydroxy-ethyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

9 3-(2-Cyclohexyl- 4,6-dioxo- piperidin-1-yl)-5- phenyl-thiophene-2-carboxylic acid

10 3-[(2R,5R)-5- Cyclohexyl-2-(2,3- dihydroxy-propyl)- 3-oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

11 3-[6-Cyclohexyl-3- hydroxy-3-(3- hydroxy-propyl)-2- oxo-piperidin-1-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

12 3-(2-Cyclohexyl- 4-hydroxy-6-oxo- piperidin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

13 3-(3-Cyclohexyl- 5-oxo-morphoIin- 4-yl)-5-phenyl- thiophene-2-carboxylic acid

14 (R)-4-(2-Carboxy- 5-phenyl- thiophen-3-yl)-3- cyclohexyl-5-oxo-piperazine-1- carboxylic acid tert-butyl ester

15 3-((R)-2- Cyclohexyl-6-oxo- piperazin-1-yl)-5- phenyl-thiophene-2-carboxylic acid

16 3-((R)-4-Benzoyl- 2-cyclohexyl-6- oxo-piperazin-1- yl)-5-phenyl-thiophene-2- carboxylic acid

17 3-((R)-4-Benzyl-2- cyclohexyl-6-oxo- piperazin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

18 3-[(R)-2- Cyclohexyl-6-oxo- 4-(toluene-4- sulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

19 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(3,3- dimethyl-but-1-ynyl)-thiophene-2- carboxylic acid

20 3-(2-Cyclohexyl- 6-oxo-4- phenylacetylamino- piperidin-1-yl)-5-phenyl- thiophene-2- carboxylic acid

21 3-[2-Cyclohexyl-6- oxo-4-(2- phenoxy- acetylamino)-piperidin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

22 3-[(2R,4S)-2- Cyclohexyl-6-oxo- 4-(2-phenoxy- acetylamino)-piperidin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

23 3-((2R,4R)-4- Amino-2- cyclohexyl-6-oxo- piperidin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

24 3-((2S,4R)-4- Benzoylamino-2- cyclohexyl-6-oxo- piperidin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

25 3-((2R,4R)-4- Benzoylamino-2- cyclohexyl-6-oxo- piperidin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

26 3-(2-Cyclohexyl- 4-methanesulfonyl- 6-oxo-piperazin-1- yl)-5-phenyl-thiophene-2- carboxylic acid

27 3-(2-Cyclohexyl- 6-oxo-4- phenylmethanesulfonyl- piperazin-1-yl)-5-phenyl- thiophene-2- carboxylic acid

28 3-((2S,4R)-4- Amino-2- cyclohexyl-6-oxo- piperidin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

29 3-[4-(3-Carboxy- 4-methoxy- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

30 3-[4-(4-Carboxy- benzenesulfonyl)- 2-cyclohexyl-6- oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

31 3-[2-Cyclohexyl-6- oxo-4-(pentane-1- sulfonyl)- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

32 3-[2-Cyclohexyl-4- (3,5-dimethyl- isoxazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

33 4-[4-(2-Carboxy- 5-phenyl- thiophen-3-yl)-3- cyclohexyl-5-oxo-piperazine-1- sulfonyl]-2,5- dimethyl-furan-3- carboxylic acid

34 3-((R)-2- Cyclohexyl-6-oxo- piperidin-1-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

35 3-((S)-2- Cyclohexyl-6-oxo- piperidin-1-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

36 3-[2-Cyclohexyl-4- (4-methyl- piperidine-1- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

37 3-[2-Cyclohexyl-6- oxo-4-(propane-2- sulfonyl)- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

38 3-[2-Cyclohexyl-4- (2-methyl- propane-1- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

39 3-[2-Cyclohexyl-6- oxo-4-(2-phenyl- ethanesulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

40 3-[2-Cyclohexyl-4- (2-fluoro- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

41 3-[4-(2-Carboxy- ethanesulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

42 3-(2-Cyclohexyl-4- cyclopentanesulfonyl- 6-oxo- piperazin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

43 3-[(2S,4R)-2- Cyclohexyl-6-oxo- 4-(toluene-4- sulfonylamino)-piperidin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

44 3-[(2R,4R)-2- Cyclohexyl-6-oxo- 4-(toluene-4- sulfonylamino)-piperidin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

45 3-[4-(Butane-2- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

46 3-(4- Cyclohexanesulfonyl- 2-cyclohexyl- 6-oxo-piperazin-1-yl)-5-phenyl- thiophene-2- carboxylic acid

47 3-[4-(2-Amino- ethanesulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

48 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(3-fluoro- phenyl)-thiophene-2- carboxylic acid

49 3-[2-Cyclohexyl-6- oxo-4-(toluene-3- sulfonyl)- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

50 3-[4-(4- Acetylamino- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

51 3-[2-Cyclohexyl-6- oxo-4-(4- phenoxy- benzenesulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

52 3-(4- Benzenesulfonyl- 2-cyclohexyl-6- oxo-piperazin-1- yl)-5-phenyl-thiophene-2- carboxylic acid

53 3-[2-Cyclohexyl-6- oxo-4-(4- trifluoromethoxy- benzenesulfonyl)-piperazin-1-yl]-5- [(Z)-1-eth-(E)- ylidene-but-2- enyl]-thiophene-2-carboxylic acid

54 3-[2-Cyclohexyl-6- oxo-4-(4- trifluoromethyl- benzenesulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

55 3-[2-Cyclohexyl-4- (4-ethyl- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

56 3-[2-Cyclohexyl-4- (4-ethyl- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

57 3-[2-Cyclohexyl-4- (1-methyl-1H- indole-7-sulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

58 3-[2-Cyclohexyl-6- oxo-4-(toluene-2- sulfonyl)- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

59 3-[2-Cyclohexyl-6- oxo-4-(3- trifluoromethoxy- benzenesulfonyl)-piperazin-1-yl]-5- [(E)-((Z)-1- propenyl)-buta- 1,3-dienyl]-thiophene-2- carboxylic acid

60 3-[4-(Biphenyl-4- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

61 3-[2-Cyclohexyl-4- (1-methyl-1H- indole-5-sulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

62 3-[2-Cyclohexyl-4- (1-methyl-1H- pyrazole-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

63 3-{2-Cyclohexyl- 4-[3-(2-methyl- pyrimidin-4-yl)- benzenesulfonyl]-6-oxo-piperazin-1- yl}-5-phenyl- thiophene-2- carboxylic acid

64 3-[2-Cyclohexyl-4- (1-methyl-1H- indole-4-sulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

65 3-[4-(Biphenyl-3- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

66 3-[2-Cyclohexyl-4- (4-fluoro-3- trifluoromethyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

67 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(2-fluoro- phenyl)-thiophene-2- carboxylic acid

68 3-[2-Cyclohexyl-6- oxo-4-(2- trifluoromethyl- benzenesulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

69 3-[2-Cyclohexyl-4- (6-diethylamino- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

70 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(4-fluoro- phenyl)-thiophene-2- carboxylic acid

71 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-p-tolyl- thiophene-2-carboxylic acid

72 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(4-ethyl- phenyl)-thiophene-2- carboxylic acid

73 5-(4-Chloro- phenyl)-3-(2- cyclohexyl-6-oxo- piperidin-1-yl)-thiophene-2- carboxylic acid

74 3-[4-(6-Azetidin-1- yl-pyridine-3- sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

75 3-[2-Cyclohexyl-4- (6-cyclohexylamino- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

76 3-[2-Cyclohexyl-6- oxo-4-(6- pyrrolidin-1-yl- pyridine-3- sulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

77 3-[2-Cyclohexyl-4- (6-dipropylamino- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

78 3-{2-Cyclohexyl- 4-[6-(2-methoxy- ethylamino)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

79 3-[2-Cyclohexyl-6- oxo-4-(6- thiomorpholin-4- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

80 3-(4-{6-[Bis-(2- methoxy-ethyl)- amino]-pyridine-3- sulfonyl}-2-cyclohexyl-6-oxo- piperazin-1-yl)-5- phenyl-thiophene- 2-carboxylic acid

81 3-{2-Cyclohexyl- 4-[6-(2- dimethylamino- ethylamino)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

82 3-[2-Cyclohexyl-4- (6-cyclopentylamino- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

83 3-(4-{6-[Bis-(2- hydroxy-ethyl)- amino]-pyridine-3- sulfonyl}-2-cyclohexyl-6-oxo- piperazin-1-yl)-5- phenyl-thiophene- 2-carboxylic acid

84 3-[2-Cyclohexyl-6- oxo-4-(3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene-2-carboxylic acid

85 3-[2-Cyclohexyl-4- (6-isopropylamino- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

86 3-{2-Cyclohexyl- 4-[6-(2-hydroxy- ethylamino)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

87 3-{2-Cyclohexyl- 4-[6-(2,6- dimethyl- morpholin-4-yl)- pyridine-3-sulfonyl]-6-oxo piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

88 3-[2-Cyclohexyl-6- oxo-4-(6- piperazin-1-yl- pyridine-3- sulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

89 3-{4-[6-(4-Acetyl- piperazin-1-yl)- pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

90 3-{2-Cyclohexyl- 6-oxo-4-[6- (tetrahydro-pyran- 4-ylamino)-pyridine-3- sulfonyl]- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylicacid

91 3-{2-Cyclohexyl- 4-[6-(cyclohexyl- methyl-amino)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

92 3-{2-Cyclohexyl- 4-[6-(2,5- dimethyl- pyrrolidin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

93 3-[2-Cyclohexyl-4- (4-hydroxy- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

94 3-[2-Cyclohexyl-4- (4-methoxy- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

95 3-[2-Cyclohexyl-4- (4,4-difluoro- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

96 3-[2-Cyclohexyl-4- (4-methyl-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

97 3-[(R)-4-(3- Cyano- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

98 3-[2-Cyclohexyl-4- (4-methylcarbamoyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

99 3-[2-Cyclohexyl-4- (4-methyl-3,4- dihydro-2H- pyrido[3,2-b][1,4]oxazine-7- sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene-2-carboxylic acid

100 3-[2-Cyclohexyl-4- (4-isopropyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

101 3-[2-Cyclohexyl-6- oxo-4-(4-pyrazol- 1-yl- benzenesulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

102 3-[2-Cyclohexyl-4- (3,4-dimethoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

103 3-[2-Cyclohexyl-4- (4-methoxy- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

104 3-[2-Cyclohexyl-4- (3-fluoro- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

105 3-[4-(4-tert-Butyl- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

106 3-[2-Cyclohexyl-4- (4-difluoromethoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

107 3-[(R)-2- Cyclohexyl-4-(3- methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

108 3-[2-Cyclohexyl-6- oxo-4-(pyridine-3- sulfonyl)- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

109 3-[2-Cyclohexyl-4- (4-fluoro- benzenesulfonyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

110 3-[2-Cyclohexyl-4- (naphthalene-1- sulfonyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

111 3-[2-Cyclohexyl-4- (2,3-dichloro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-phenyl- thiophene-2- carboxylic acid

112 4-[4-(2-Carboxy- 5-phenyl- thiophen-3-yl)-3- cyclohexyl-5-oxo-piperazine-1- sulfonyl]- piperidine-1- carboxylic acid benzyl ester

113 5-(4-tert-Butyl- phenyl)-3-(2- cyclohexyl-6-oxo- piperidin-1-yl)-thiophene-2- carboxylic acid

114 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(4-methoxy- phenyl)-thiophene-2- carboxylic acid

115 3-[(R)-5- Cyclohexyl-2,2- bis-(3-hydroxy- propyl)-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

116 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(4-ethoxy- phenyl)-thiophene-2- carboxylic acid

117 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-(4- trifluoromethyl-phenyl)- thiophene-2- carboxylic acid

118 3-{2-Cyclohexyl- 4-[6-((R)-2- methyl-pyrrolidin- 1-yl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

119 3-{2-Cyclohexyl- 4-[6-((S)-2- methyl-pyrrolidin- 1-yl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

120 3-{2-Cyclohexyl- 4-[6-((R)-3-fluoro- pyrrolidin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

121 3-{2-Cyclohexyl- 4-[6-((S)-3-fluoro- pyrrolidin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

122 3-{2-Cyclohexyl- 4-[6-((2R,4R)-4- hydroxy-2-methyl-pyrrolidin-1-yl)- pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5-phenyl-thiophene- 2-carboxylic acid

123 3-{2-Cyclohexyl- 4-[6-((R)-3- hydroxy- pyrrolidin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

124 3-{2-Cyclohexyl- 4-[6-((S)-3- hydroxy- pyrrolidin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

125 3-{4-[6-(7-Aza- bicyclo[2.2.1]hept- 7-yl)-pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

126 3-[2-Cyclohexyl-4- ((2S,6R)-2,6- dimethyl-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

127 3-{2-Cyclohexyl- 4-[4-((R)-2- methyl-pyrrolidin- 1-yl)-benzenesulfonyl]- 6-oxo-piperazin-1- yl}-5-phenyl- thiophene-2-carboxylic acid

128 3-[6-Cyclohexyl-3- methyl-4-(6- morpholin-4-yl- pyridine-3-sulfonyl)-2-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

129 5-(4-Cyano- phenyl)-3-(2- cyclohexyl-6-oxo- piperidin-1-yl)-thiophene-2- carboxylic acid

130 3-{(R)-2- Cyclohexyl-4-[6- ((R)-2-methyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

131 3-{(S)-2- Cyclohexyl-4-[6- ((R)-2-methyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

132 3-[(S)-2- Cyclohexyl-6-oxo- 4-(6-piperazin-1- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

133 5-(3-Chloro- phenyl)-3-(2- cyclohexyl-6-oxo- piperidin-1-yl)-thiophene-2- carboxylic acid

134 3-(2-Cyclohexyl- 6-oxo-piperidin-1- yl)-5-m-tolyl- thiophene-2-carboxylic acid

135 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-pyrrolidin-1- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

136 3-[(S)-2- Cyclohexyl-6-oxo- 4-(6-pyrrolidin-1- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

137 3-{(R)-2- Cyclohexyl-4-[6- (4-methyl- piperazin-1-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

138 3-[(R)-4-(4- Amino-4-methyl- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

139 3-{(R)-2- Cyclohexyl-4-[6- ((S)-3- hydroxymethyl- piperazin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

140 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3-methyl- piperazin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

141 3-{(R)-4-[6-((R)-3- Amino-pyrrolidin- 1-yl)-pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

142 3-[(R)-4-((S)-3- Amino-3,4,5,6- tetrahydro-2H- [1,2′]bipyridinyl-5′-sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5- phenyl-thiophene-2-carboxylic acid

143 3-[(R)-4-(4- Aminomethyl- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

144 3-{(R)-4-[6-((S)-3- Amino-pyrrolidin- 1-yl)-pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

145 3-{(R)-2- Cyclohexyl-4-[6- ((S)-3-methyl- piperazin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

146 3-{(R)-4-[6-((R)-3- tert- Butoxycarbonyl- amino-pyrrolidin-1-yl)-pyridine-3- sulfonyl]-2- cyclohexyl-6-oxo- piperazin-1-yl}-5-phenyl-thiophene- 2-carboxylic acid

147 3-[(R)-2- Cyclohexyl-4-(4- dimethylamino- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

148 3-{(R)-2- Cyclohexyl-4-[6- (4-ethyl-piperazin- 1-yl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

149 3-{(R)-4-[4-(tert- Butoxycarbonyl- amino-methyl)-3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-5′- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

150 3-{(R)-2- Cyclohexyl-4-[6- ((3R,5S)-3,5- dimethyl- piperazin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

151 (R)-4-{5-[(R)-4-(2- Carboxy-5- phenyl-thiophen- 3-yl)-3-cyclohexyl-5-oxo-piperazine- 1-sulfonyl]- pyridin-2-yl}-2- methyl- piperazine-1-carboxylic acid tert-butyl ester

152 3-{(R)-4-[6-(4-tert- Butyl-piperazin-1- yl)-pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

153 3-[(R)-4-(4-tert- Butoxycarbonylamino- 4-methyl-3,4,5,6-tetrahydro-2H- [1,2′]bipyridinyl-5′- sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

154 3-{(R)-2- Cyclohexyl-4-[6- (2-ethyl-pyrrolidin- 1-yl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

155 3-[(R)-2- Cyclohexyl-4-(3- dimethylamino- 3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

156 3-{(R)-2- Cyclohexyl-4-[6- ((S)-3- dimethylamino- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

157 3-{(R)-2- Cyclohexyl-4-[6- (hexahydro- pyrrolo[1,2-a] pyrazin-2-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

158 3-[(R)-4-((S)-3- tert- Butoxycarbonylamino- 3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

159 3-[(R)-4-((S)-3- tert- Butoxycarbonyl- amino-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-2- cyclohexyl-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

160 3-{(R)-2- Cyclohexyl-4-[6- (4-isopropyl- piperazin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

161 (R)-4-{5-[(R)-4-(2- Carboxy-5- phenyl-thiophen- 3-yl)-3-cyclohexyl-5-oxo-piperazine- 1-sulfonyl]- pyridin-2-yl}-2- hydroxymethyl-piperazine-1- carboxylic acid tert-butyl ester

162 (S)-4-{5-[(R)-4-(2- Carboxy-5- phenyl-thiophen- 3-yl)-3-cyclohexyl-5-oxo-piperazine- 1-sulfonyl]- pyridin-2-yl}-2- methyl- piperazine-1-carboxylic acid tert-butyl ester

163 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3- dimethylamino- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

164 3-{(R)-2- Cyclohexyl-4-[6- ((2S,5R)-2,5- dimethyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

165 3-{(R)-4-[6-((S)-3- tert- Butoxycarbonylamino- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-2- cyclohexyl-6-oxo- piperazin-1-yl}-5-phenyl-thiophene- 2-carboxylic acid

166 3-[2-Cyclohexyl-6- oxo-4-(toluene-4- sulfonyl)- piperazin-1-yl]-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

167 3-{(R)-2- Cyclohexyl-4-[6- ((2R,6S)-2,6- dimethyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

168 3-[2-Cyclohexyl-4- (6-morpholin-4-yl- pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

169

170 3-{(R)-4-[5- Chloro-6-((R)-2- methyl-pyrrolidin- 1-yl)-pyridine-3-sulfonyl]-2- cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

171 3-{(R)-2- Cyclohexyl-4-[6- ((S)-2- methoxymethyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

172 3-[(R)-2- Cyclohexyl-4-(5- methyl-6- pyrrolidin-1-yl- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

173 3-{(R)-2- Cyclohexyl-4-[5- methyl-6-((R)-2- methyl-pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

174 3-[2-Cyclohexyl-4- (4-methyl-benzyl)- 6-oxo-piperazin-1- yl]-5-(3,3-dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

175 3-(2-Cyclohexyl- 6-oxo-piperazin-1- yl)-5-(3,3- dimethyl-but-1-ynyl)-thiophene-2- carboxylic acid

176 3-[(R)-2- Cyclohexyl-4-(4- isopropyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

177 3-[(R)-2- Cyclohexyl-4-(6- diethylamino- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

178 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-phenyl- pyridine-3- sulfonyl)-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

179 3-[(R)-2- Cyclohexyl-6-oxo- 4-(3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene-2-carboxylic acid

180 3-{(R)-2- Cyclohexyl-4-[6- ((R)-2-methyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- p-tolyl-thiophene-2-carboxylic acid

181 3-((R)-4- Cyclohexyl-2-oxo- oxazolidin-3-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

182 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-pyrrolidin-1- yl-pyridin-3-ylmethyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

183 3-[(R)-2- Cyclohexyl-4-((R)- 2-methyl-3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)-6-oxo- piperazin-1-yl]-5-phenyl-thiophene- 2-carboxylic acid

184 3-[(R)-2- Cyclohexyl-4-(6- morpholin-4-yl- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

185 3-{(R)-2- Cyclohexyl-4-[6- ((R)-2-methyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

186 3-[(R)-2- Cyclohexyl-4-(6- [1,4]oxazepan-4- yl-pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- (4-fluoro-phenyl)- thiophene-2-carboxylic acid

187 3-[(R)-2- Cyclohexyl-4-(6- morpholin-4-yl- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

188 3-[(R)-2- Cyclohexyl-4-(6- [1,4]oxazepan-4- yl-pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

189 3-[(R)-2- Cyclohexyl-4-(6- morpholin-4-yl- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- (4-fluoro-phenyl)- thiophene-2-carboxylic acid

190 3-[(R)-2- Cyclohexyl-4-(4- methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

191 3-[(R)-2- Cyclohexyl-4-(6- methoxy-pyridine- 3-sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

192 3-[(R)-2- Cyclohexyl-6-oxo- 4-(pyridine-3- sulfonyl)-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

193 3-[(R)-2- Cyclohexyl-4-(1- methyl-1H- pyrazole-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

194 3-{(R)-2- Cyclohexyl-6-oxo- 4-[6-(tetrahydro- pyran-4-ylamino)-pyridine-3- sulfonyl]- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylicacid

195 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3-methyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

196 3-{(R)-2- Cyclohexyl-4-[6- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

197 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3-methyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- p-tolyl-thiophene-2-carboxylic acid

198 3-{(R)-2- Cyclohexyl-4-[6- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- p-tolyl-thiophene-2-carboxylic acid

199 5-(4-Chloro- phenyl)-3-[(R)-2- cyclohexyl-4-(6- morpholin-4-yl-pyridine-3- sulfonyl)-6-oxo- piperazin-1-yl]- thiophene-2- carboxylicacid

200 5-(4-Chloro- phenyl)-3-[(R)-2- cyclohexyl-4-(6- [1,4]oxazepan-4-yl-pyridine-3- sulfonyl)-6-oxo- piperazin-1-yl]- thiophene-2- carboxylicacid

201 5-(4-Chloro- phenyl)-3-{(R)-2- cyc!ohexyl-4-[6- ((R)-2-methyl-pyrrolidin-1-yl)- pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-thiophene-2- carboxylic acid

202 3-((R)-2- Cyclohexyl-4-{6- [4-(4-methyl- piperazine-1-carbonyl)-phenyl]- pyridine-3- sulfonyl)-6-oxo- piperazin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

203 3-{(R)-2- Cyclohexyl-4-[6- (4-dimethylamino- phenyl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylicacid

204 3-[(R)-2- Cyclohexyl-4-(4′- methoxy- [2,3′]bipyridinyl-5-sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

205 3-{(R)-2- Cyclohexyl-4-[6- (2,4-difluoro- phenyl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylicacid

206 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-pyrimidin-5- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

207 3-[(R)-4- ([2,4′]Bipyridinyl- 5-sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- [(E)-((Z)-1- propenyl)-buta- 1,3-dienyl]-thiophene-2- carboxylic acid

208 3-{(R)-2- Cyclohexyl-4-[6- (4-morpholin-4- ylmethyl-phenyl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

209 3-{(R)-2- Cyclohexyl-6-oxo- 4-[6-(2H-pyrazol- 3-yl)-pyridine-3-sulfonyl]- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

210 3-{(R)-4-[6-(5- Carboxy- thiophen-2-yl)- pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

211 3-{(R)-2- Cyclohexyl-4-[6- (2-methyl-furan-3- yl)-pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

212 3-{(R)-2- Cyclohexyl-4-[6- (3,4-dihydro-2H- benzo[b][1,4]dioxepin-7-yl)- pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5-phenyl-thiophene- 2-carboxylic acid

213 3-{(R)-4-[6-(2- Cyano-phenyl)- pyridine-3- sulfonyl]-2-cyclohexyl-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

214 3-[(R)-4- ([2,3′]Bipyridinyl- 5-sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

215 3-[(R)-2- Cyclohexyl-4-(6- cyclopent-1-enyl- pyridine-3-sulfonyl)-6-oxo- piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

216 3-{(R)-2- Cyclohexyl-4-[6- (8-oxa-3-aza- bicyclo[3.2.1]oct-3-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

217 3-{(R)-2- Cyclohexyl-4-[6- (2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

218 3-{(R)-2- Cyclohexyl-4-[6- (2,2-diethyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

219 3-{(R)-2- Cyclohexyl-4-[6- (3,3-dimethyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

220 3-(2-Cyclohexyl- 5-oxo-pyrrolidin-1- yl)-5-(3,3- dimethyl-but-1-ynyl)-thiophene-2- carboxylic acid

221 3-[(R)-2- Cyclohexyl-6-oxo- 4-(propane-2- sulfonyl)-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

222 3-{(R)-2- Cyclohexyl-4-[6- (1-methyl-1H- pyrazol-4-yl)- pyridine-3-sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene- 2-carboxylic acid

223 3-[(R)-2- Cyclohexyl-6-oxo- 4-(4- trifluoromethoxy-benzenesulfonyl)- piperazin-1-yl]-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

224 3-{(R)-2- Cyclohexyl-4-[6′- (4-methyl- piperazin-1-yl)-[2,3′]bipyridinyl-5- sulfonyl]-6-oxo- piperazin-1-yl}-5-phenyl-thiophene- 2-carboxylic acid

225 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3-methyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- phenyl-thiophene-2-carboxylic acid

226 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4-[6- ((R)-3-methyl-morpholin-4-yl)- pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-thiophene-2- carboxylic acid

227 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4-[6- (8-oxa-3-aza-bicyclo[3.2.1]oct- 3-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-thiophene-2- carboxylic acid

228 3-{(R)-2- Cyclohexyl-4-[6- (2-oxa-5-aza- bicyclo[2.2.1]hept-5-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

229 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4-[6- (2-oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-thiophene-2- carboxylic acid

230 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6- trifluoromethyl- pyridine-3-sulfonyl)- piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene-2-carboxylic acid

231 5-(4-Chloro- phenyl)-3-[(R)-2- cyclohexyl-6-oxo-4-(4-pyrrolidin-1-yl- benzenesulfonyl)- piperazin-1-yl]- thiophene-2-carboxylic acid

232 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-pyrrolidin-1- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- (4-fluoro-phenyl)- thiophene-2- carboxylicacid

233 5-(4-Chloro- phenyl)-3-[(R)-2- cyclohexyl-6-oxo-4-(4-piperidin-1-yl- benzenesulfonyl)- piperazin-1-yl]- thiophene-2-carboxylic acid

234 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4-[4- ((R)-2-methyl-pyrrolidin-1-yl)- benzenesulfonyl]- 6-oxo-piperazin-1- yl}-thiophene-2-carboxylic acid

235 3-[(R)-2- Cyclohexyl-6-oxo- 4-(3,4,5,6- tetrahydro-2H-[1,2′]bipyridinyl-5′- sulfonyl)- piperazin-1-yl]-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

236 3-((R)-3- Cyclohexyl-5-oxo- morpholin-4-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

237 3-((4S,5R)-5- Cyclohexyl-3,4- dimethyl-2-oxo- imidazolidin-1-yl)-5-(3,3-dimethyl- but-1-ynyl)- thiophene-2- carboxylic acid

238 3-[(R)-4-(4- Cyano- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

239 3-[(R)-2- Cyclohexyl-4-(3- fluoro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

240 3-[(R)-2- Cyclohexyl-4-(5- methyl-isoxazole- 4-sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

241 3-[(R)-2- Cyclohexyl-6-oxo- 4-(1H-pyrazole-4- sulfonyl)-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

242 3-[(R)-4-(3- Chloro benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

243 3-[(R)-2- Cyclohexyl-4-(4- fluoro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

244 3-[(R)-2- Cyclohexyl-4-(2,4- dimethyl-thiazole- 5-sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

245 3-((R)-2- Cyclohexyl-4- cyclopropanesulfonyl- 6-oxo-piperazin-1-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

246 3-[(R)-2- Cyclohexyl-4-(3- fluoro-4-methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

247 3-[(R)-2- Cyclohexyl-4-(1H- imidazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

248 3-[(R)-2- Cyclohexyl-4-(1,2- dimethyl-1H- imidazole-4-sulfonyl)-6-oxo piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene-2-carboxylic acid

249 3-[(R)-2- Cyclohexyl-6-oxo- 4-(2- trifluoromethoxy-benzenesulfonyl)- piperazin-1-yl]-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

250 3-[(R)-2- Cyclohexyl-6-oxo- 4-(4- trifluoromethyl- benzenesulfonyl)-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

251 3-[(R)-2- Cyclohexyl-4-(2,6- difluoro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

252 3-[(R)-2- Cyclohexyl-6-oxo- 4-(2-oxo-2,3- dihydro- benzooxazole-5-sulfonyl)- piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene-2-carboxylic acid

253 3-[(R)-2- Cyclohexyl-4-(4- methylcarbamoyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

254 3-[(R)-2- Cyclohexyl-4-(2- methyl-2H- pyrazole-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

255 3-[(R)-2- Cyclohexyl-4-(2,3- dimethyl-3H- imidazole-4-sulfonyl)-6-oxo- piperazin-1-yl]-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

256 3-[(R)-2- Cyclohexyl-4-(4- ethyl- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

257 3-[(R)-2- Cyclohexyl-4-(3- methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

258 3-[(R)-2- Cyclohexyl-4-(2- methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

259 3-[(R)-4-(3- Cyano- benzenesulfonyl)- 2-cyclohexyl-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

260 3-[(R)-2- Cyclohexyl-4-(1,3- dimethyl-1H- pyrazole-4-sulfonyl)-6-oxo- piperazin-1-yl]-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

261 3-[(R)-2- Cyclohexyl-6-oxo- 4-(3-pyrrol-1-yl- benzyl)-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

262 3-{(R)-2- Cyclohexyl-6-oxo- 4-[4-(2-oxo- pyrrolidin-1-yl)-benzyl]-piperazin- 1-yl}-5-phenyl- thiophene-2- carboxylic acid

263 3-[(R)-2- Cyclohexyl-4-(3- methyl-benzyl)-6- oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

264 3-[(R)-2- Cyclohexyl-4-(2,6- dimethyl-benzyl)- 6-oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

265 3-((R)-2- Cyclohexyl-4- cyclohexylmethyl- 6-oxo-piperazin-1-yl)-5-phenyl- thiophene-2- carboxylic acid

266 3-[(R)-2- Cyclohexyl-4-(3- fluoro-2- morpholin-4-yl- benzyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

267 3-[(R)-4-(6- Chloro-pyridin-3- ylmethyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

268 3-((R)-2- Cyclohexyl-6-oxo- 4-phenethyl- piperazin-1-yl)-5-phenyl-thiophene- 2-carboxylic acid

269 3-[(R)-2- Cyclohexyl-4-(2- methyl-benzyl)-6- oxo-piperazin-1-yl]-5-phenyl- thiophene-2- carboxylic acid

270 3-[(R)-2- Cyclohexyl-4-(4- dimethylamino- benzyl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

271 3-[(R)-2- Cyclohexyl-4-(1- methyl-piperidin- 4-yl)-6-oxo-piperazin-1-yl]-5- phenyl-thiophene- 2-carboxylic acid

272 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6-pyrrolidin-1- yl-pyridine-3-sulfonyl)- piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

273 3-{(R)-2- Cyclohexyl-4- [(1R,4R)-6-(2- oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-pyridine-3- sulfonyl]-6-oxo-piperazin-1-yl}-5- (4-fluoro-phenyl)- thiophene-2- carboxylic acid

274 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4- [(1R,4R)-6-(2-oxa-5-aza- bicyclo[2.2.1]hept- 5-yl)-pyridine-3- sulfonyl]-6-oxo-piperazin-1-yl}- thiophene-2- carboxylic acid

275 3-[(R)-2- Cyclohexyl-4-(1- ethyl-1H- pyrazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

276 3-[(R)-2- Cyclohexyl-4-(2- fluoro-4,5- dimethoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

277 3-[(R)-2- Cyclohexyl-4-(3,4- dimethoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

278 3-{(R)-2- Cyclohexyl-4-[6- ((2R,6S)-2,6- dimethyl- morpholin-4-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

279 3-{(R)-2- Cyclohexyl-4-[6- ((S)-2- methoxymethyl- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

280 3-{(R)-2- Cyclohexyl-4-[6- ((R)-3-fluoro- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

281 3-[(R)-2- Cyclohexyl-4-(2,4- difluoro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

282 3-[(R)-2- Cyclohexyl-4-(2,6- dichloro- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

283 3-[(R)-2- Cyclohexyl-4-(4- fluoro-3-methoxy- benzenesulfonyl)-6-oxo-piperazin-1- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

284 5-(4-Chloro- phenyl)-3-[(R)-2- cyclohexyl-4-(1- methyl-1H-pyrazole-3- sulfonyl)-6-oxo- piperazin-1-yl]- thiophene-2- carboxylicacid

285 3-[(R)-4-(6- Azepan-1-yl- pyridine-3- sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- (4-fluoro-phenyl)- thiophene-2- carboxylic acid

286 3-{(R)-2- Cyclohexyl-4-[6- (3,3-difluoro- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

287 3-{(R)-2- Cyclohexyl-4-[6- ((S)-3-fluoro- pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

288 3-{(R)-2- Cyclohexyl-4-[6- (3-hydroxy-3- methyl-pyrrolidin-1-yl)-pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-5- (4-fluoro-phenyl)-thiophene-2- carboxylic acid

289 3-{(R)-2- Cyclohexyl-4- [(1R,4R)-6-(2- oxa-5-aza-bicyclo[2.2.1]hept- 5-yl)-pyridine-3- sulfonyl]-6-oxo-piperazin-1-yl}-5- p-tolyl-thiophene- 2-carboxylic acid

290 3-((R)-5- Cyclohexyl-2,2- dimethyl-3-oxo morpholin-4-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

291 3-((2R,3R)-3- Cyclohexyl-2- methyl-5-oxo- morpholin-4-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

292 5-(4-Chloro- phenyl)-3-{(R)-2- cyclohexyl-4-[6- (3,3-dimethyl-pyrrolidin-1-yl)- pyridine-3- sulfonyl]-6-oxo- piperazin-1-yl}-thiophene-2- carboxylic acid

293 5-(4-Chloro- phenyl)-3-((R)-3- cyclohexyl-5-oxo- morpholin-4-yl)-thiophene-2- carboxylic acid

294 3-[(R)-5- Cyclohexyl-2-(2- morpholin-4-yl-2- oxo-ethyl)-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

295 3-[(R)-2- Cyclohexyl-4-(1- methyl-1H- pyrazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

296 3-[(R)-2- Cyclohexyl-4-(1- ethyl-1H- pyrazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

297 3-[(R)-2- Cyclohexyl-4-(1- methyl-1H- imidazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

298 3-[(R)-2- Cyclohexyl-4-(1,2- dimethyl-1H- imidazole-4-sulfonyl)-6-oxo- piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

299 3-[(R)-5- Cyclohexyl-2-(3- hydroxy-propyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

300 3-[(R)-2- Cyclohexyl-6-oxo- 4-(6- trifluoromethyl- pyridine-3-sulfonyl)- piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

301 3-[(R)-2- Cyclohexyl-4-(1- isobutyl-1H- pyrazole-4- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

302 3-[(R)-2- Cyclohexyl-4-(6- methyl-pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

303 3-[(R)-4-(6-tert- Butyl-pyridine-3- sulfonyl)-2- cyclohexyl-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

304 3-[(R)-2- Cyclohexyl-4-(6- ethyl-pyridine-3- sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

305 3-[(R)-2- Cyclohexyl-4-(5,6- dimethyl-pyridine- 3-sulfonyl)-6-oxo-piperazin-1-yl]-5- p-tolyl-thiophene- 2-carboxylic acid

306 3-[(R)-5- Cyclohexyl-2-(3- methanesulfonyl- propyl)-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

307 3-{(R)-5- Cyclohexyl-2-[(2- methoxy- ethylamino)- methyl]-3-oxo-morpholin-4-yl}-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

308 3-(4-Cyclohexyl- 2-oxo- [1,3]oxazinan-3- yl)-5-(3,3- dimethyl-but-1-ynyl)-thiophene-2- carboxylic acid

309 N-[3-((R)-3- Cyclohexyl-5-oxo- morpholin-4-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carbonyl]- methanesulfonamide

310 3-((R)-5- Cyclohexyl-2- morpholin-4- ylmethyl-3-oxo-morpholin-4-yl)-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

311 3-[(2R,5R)-5- Cyclohexyl-2-(3- hydroxy-propyl)-2- methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

312 3-((2S,5R)-2- Cyanomethyl-5- cyclohexyl-2- methyl-3-oxo-morpholin-4-yl)-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

313 3-(6-Cyclohexyl- 3-hydroxy-2-oxo- piperidin-1-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

314 3-((R)-5- Cyclohexyl-2,2- dimethyl-3-oxo- morpholin-4-yl)-5-p-tolyl-thiophene- 2-carboxylic acid

315 5-(4-Chloro- phenyl)-3-((R)-5- cyclohexyl-2,2- dimethyl-3-oxo-morpholin-4-yl)- thiophene-2- carboxylic acid

316 3-[6-Cyclohexyl-3- (1-hydroxy-ethyl)- 2-oxo-piperidin-1- yl]-5-(3,3-dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

317 3-(6-Cyclohexyl- 3-hydroxy-2-oxo- piperidin-1-yl)-5-p-tolyl-thiophene- 2-carboxylic acid

318 3-[(2S,5R)-5- Cyclohexyl-2-(3- hydroxy-3-methyl- butyl)-2-methyl-3-oxo-morpholin-4- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

319 3-[(2R,5R)-5- Cyclohexyl-2-(3- hydroxy-3-methyl- butyl)-2-methyl-3-oxo-morpholin-4- yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2-carboxylic acid

320 3-[(2S,5R)-5- Cyclohexyl-2-((R)- 3-hydroxy-butyl)- 2-methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

321 3-[(2R,5R)-5- Cyclohexyl-2-((R)- 3-hydroxy-butyl)- 2-methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

322 3-((3S,6S)-6- Cyclohexyl-3- hydroxy-2-oxo- piperidin-1-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

323 3-[(2R,5R)-5- Cyclohexyl-2-(2- hydroxy-ethyl)-2- methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

324 3-(6-Cyclohexyl- 3-hydroxy-3- methyl-2-oxo- piperidin-1-yl)-5-p-tolyl-thiophene- 2-carboxylic acid

325 3-((R)-3- Cyclohexyl-5-oxo- 1,9-dioxa-4-aza- spiro[5.5]undec-4-yl)-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

326 3-[(2S,5R)-5- Cyclohexyl-2-(2,3- dihydroxy-propyl)- 2-methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

327 3-[(2S,5R)-5- Cyclohexyl-2-(2,3- dihydroxy-propyl)- 2-methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

328 3-[(2S,5R)-5- Cyclohexyl-2-(2- hydroxy-ethyl)-2- methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

329 3-((R)-5- Cyclohexyl-2- hydroxymethyl-3- oxo-morpholin-4-yl)-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

330 3-[(2R,5R)-5- Cyclohexyl-2-(2,3- dihydroxy-propyl)- 2-methyl-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

331 3-[(2S,5R)-5- Cyclohexyl-2-(2,3 dihydroxy-propyl)- 3-oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2 carboxylic acid

332 3-[(2S,5R)-5- Cyclohexyl-2-(2- hydroxy-ethyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

333 3-[(R)-5- Cyclohexyl-2,2- bis-(2-hydroxy- ethyl)-3-oxo-morpholin-4-yl]-5- (3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylicacid

334 3-((3R,6S)-6- Cyclohexyl-3- hydroxy-2-oxo- piperidin-1-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

335 3-((S)-2- Cyclohexyl-7-oxo- azepan-1-yl)-5- (3,3-dimethyl-but-1-ynyl)-thiophene- 2-carboxylic acid

336 3-[(2R,5R)-5- Cyclohexyl-2-((R)- 2-hydroxy-propyl)- 3-oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

337 3-[(2R,5R)-5- Cyclohexyl-2-((S)- 2-hydroxy-propyl)- 3-oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

338 3-[(2S,5R)-5- Cyclohexyl-2-(4- hydroxy-butyl)-3- oxo-morpholin-4-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

339 3-[(S)-6- Cyclohexyl-3-(3- hydroxy-propyl)-2- oxo-piperidin-1-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

340 3-((S)-3-Amino-6- cyclohexyl-2-oxo- piperidin-1-yl)-5-(3,3-dimethyl-but- 1-ynyl)-thiophene- 2-carboxylic acid

341 3-[(S)-6- Cyclohexyl-3-(3- hydroxy-propyl)-2- oxo-piperidin-1-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

342 3-[(S)-6- Cyclohexyl-3-(2- hydroxy-ethyl)-2- oxo-piperidin-1-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

343 3-[(S)-6- Cyclohexyl-3-(2- hydroxy-ethyl)-2- oxo-piperidin-1-yl]-5-(3,3- dimethyl-but-1- ynyl)-thiophene-2- carboxylic acid

NMR data for certain compounds of the invention are provided in Table 2.

TABLE 2 Compound number NMR data 1 ¹H-NMR (400 MHz, CD₃OD): 7.80 (d,2H), 7.40 (t, 2H), 7.29 (t, 1H), 7.18 (s, 1H), 4.62 (m, 1H), 2.30 (m,2H), 2.03 (m, 1H), 1.80-1.10 (m, 12H) 2 ¹H-NMR (400 MHz, CD₃OD): δ 6.97(s, 1H), 4.13 (m, 1H), 3.90 (m, 1H), 3.82 (m, 1H), 3.57 (m, 2H),1.97-1.48 (m, 10H), 1.32 (s, 9H), 1.26-1.09 (m, 6H). 3 ¹H-NMR (400 MHz,CD₃OD): δ 6.93 (s, 1H), 4.14 (m, 1H), 4.0 (m, 1H), 3.62 (m, 1H), 3.58(m, 2H), 2.02-1.48 (m, 10H), 1.32 (s, 9H), 1.25-1.17 (m, 6H). 4 ¹H-NMR(400 MHz, CDCl₃): δ 7.43 (m, 2H), 7.21 (m, 3H), 6.94 (m, 1H), 3.68 (m,1H), 2.45 (m, 2H), 2.21 (m, 1H), 1.83-1.51 (m, 12H), 1.32 (m, 2H). 5 1HNMR (400 MHz, CDCl₃): δ 0.88-1.12 (m, 5H), 1.29 (m, 2H), 1.37 (s, 3H),1.48-1.60 (m, 2H), 1.71 (m, 2H), 1.84 (m, 2H), 1.96 (m, 1H), 2.12 (m,1H), 2.29 (s, 3H), 3.72 (m, 1H), 6.93 (s, 1H), 7.11 (d, 2H), 7.39 (d,2H) 6 ¹H-NMR (400 MHz, DMSO-d₆): δ 13.1 (s, 1H), 7.75 (d, 2H), 7.58 (s,1H), 7.37-7.52 (m, 3H), 4.21 (m, 1H), 2.34 (m, 2H), 2.09 (m, 1H), 1.91(m, 1H), 1.36-1.79 (m, 5H), 0.91-1.31 (m, 6H). 7 ¹H-NMR (400 MHz,CD₃OD): δ 6.93 (s, 1H),4.12 (d, 1H), 3.91 (d, 1H), 3.66 (s, 1H), 3.54(t, 2H), 2.14 (m, 1H), 1.91 (m, 1H), 1.44-1.85 (m, 8H), 1.41 (s, 3H),1.06-1.37 (m, 14H) 8 ¹H-NMR (400 MHz, CD₃OD): δ 6.90 (s, 1H), 4.24(tert, 1H), 4.13 (d, 1H), 4.01 (tert, 1H), 3.73 (d, 1H), 3.71 (d, 1H),3.66 (t, 1H), 2.21 (m, 1H), 1.41-1.98 (m, 8H), 1.05-1.37 (m, 15H). 10¹H-NMR (400 MHz, DMSO-d₆): δ 7.57 (s, 1H), 7.32-7.45 (m, 6H), 7.28 (t,3H), 7.20 (t, 1H), 5.45 (m, 1H), 2.52-2.63 (m, 3H), 1.89 (m, 1H). 11¹H-NMR (400 MHz, CD₃OD): δ 6.89 (s, 1H), 3.94 (m, 1H), 3.58 (m, 2H),2.05 (m, 1H), 1.92-1.39 (m, 13H), 1.32 (s, 9H), 1.25-1.13 (m, 5H) 13¹H-NMR (400 MHz, CDCl₃): δ 7.56 (d, 2H), 7.35 (m, 3H), 7.12 (s, 1H),4.26 (tert, 2H), 3.98 (m, 2H), 3.60 (s, 1H), 0.94-1.93 (m, 11H) 18¹H-NMR (400 MHz, CD₃OD): δ 7.74 (d, 2H), 7.65 (d, 2H), 7.49 (d, 2H),7.41 (t, 2H), 7.33 (t, 1H), 7.21 (s, 1H), 4.12 (d, 1H), 3.95 (d, 1H),3.93 (s, 1H), 3.37 (d, 1H), 3.02 (tert, 1H), 2.47 (s, 3H), 1.41-1.99 (m,7H), 1.05-1.32 (m, 4H) 22 ¹H-NMR (400 MHz, DMSO): δ 10.31 (d, 1H), 7.63(d, 2H), 7.42 (t, 2H), 7.31 (t, 2H), 7.23 (m, 2H), 7.14 (s, 1H), 6.98(m, 3H), 4.61 (m, 2H), 4.45 (m, 1H), 4.10 (m, 1H), 3.32 (s, 2H), 2.20(m, 1H), 1.88-1.76 (m, 4H), 1.65-1.58 (m, 2H), 1.41-1.05 (m, 6H) 23¹H-NMR (400 MHz, DMSO): δ 8.55 (m, 2H), 7.63 (d, 2H), 7.48 (t, 2H), 7.32(t, 2H), 7.15 (s, 1H), 5.76 (s, 1H), 3.98 (m, 1H), 3.82 (m, 1H), 2.33(m, 2H), 2.07 (m, 1H), 1.80 (m, 2H), 1.61 (m, 3H), 1.38 (m, 2H), 1.03(m, 5H) 35 ¹H-NMR (400 MHz, CD₃OD): δ 7.03 (s, 1H), 3.81 (m, 1H), 2.25(m, 1H), 1.88-1.38 (m, 6H), 1.29 (s, 9H), 1.18 (m, 4H), 1.06 (m, 4H) 62¹H-NMR (400 MHz, CD₃OD): δ 7.82 (d, 1H), 7.68 (d, 2H), 7.44 (m, 3H),7.36 (s, 1H), 6.78 (d, 1H), 4.16 (d, 1H), 4.02 (s, 3H), 3.94 (d, 1H),3.81 (s, 1H), 3.65 (d, 1H), 3.18 (tert, 1H), 2.00 (d, 1H), 1.36-1.87 (m,6H), 1.05-1.29 (m, 4H) 135 ¹H-NMR (400 MHz, CD₃OD): δ 8.47 (d, 1H), 7.85(tert, 1H), 7.64 (d, 2H), 7.43 (t, 2H), 7.30 (m, 2H), 6.61 (d, 1H), 3.94(s, 1H), 3.88 (d, 1H), 3.74 (d, 1H), 2.81-3.24 (m, 6H), 1.49-2.06 (m,8H), 0.98-1.35 (m, 7H) 184 ¹H-NMR (400 MHz, CD₃OD): δ 8.51 (d, 1H), 7.86(tert, 1H), 7.64 (d, 2H), 7.41 (t, 2H), 7.32 (t, 1H), 7.19 (s, 1H), 7.91(d, 1H), 4.10 (d, 1H), 3.96 (s, 1H), 3.89 (d, 1H), 3.65-3.81 (m, 8H),3.41 (d, 1H), 3.06 (d, 1H), 1.37-1.98 (m, 8H), 1.03-1.26 (m, 3H) 185 1HNMR (400 MHz, CDCl₃): δ 1.03 (m, 3H), 1.15 (d, 3H), 1.30 (m, 1H), 1.43(m, 2H), 1.58 (m, 2H), 1.63 (m, 1H), 1.7-1.8 (m, 2H), 1.9 (d, 1H),1.95-2.10 (m, 3H), 2.96 (d, 1H), 3.33 (d, 2H), 3.60 (s, 1H), 3.75 (s,1H), 3.81 (d, 1H), 4.05 (s, 1H), 4.20 (d, 1H), 6.37 (d, 1H), 7.02-7.05(m, 3H), 7.50-7.54 (m, 2H), 7.66 (m, 1H), 8.38 (s, 1H) 193 ¹H-NMR (400MHz, CD₃OD): δ 7.80 (d, 1H), 6.95 (s, 1H), 6.75 (d, 1H), 4.14 (d, 1H),3.93 (d, 1H), 3.64 (d, 1H), 3.16 (m, 1H), 2.30 (m, 2H), 1.90 (m, 1H),1.83 (m, 3H), 1.69 (m, 2H), 1.58 (t, 3H), 1.47 (m, 2H), 1.31 (s, 9H),1.18 (m, 4H) 196 1H NMR (400 MHz, CDCl₃): δ 0.95-1.15 (m, 4H), 1.20 (m,1H), 1.30-1.40 (m, 1H), 1.47 (m, 1H), 1.57 (m, 2H), 1.66 (s, 1H),1.70-1.85 (m, 3H), 1.85-1.95 (m, 2H), 3.03 (m, 1H), 3.18 (d, 2H), 3.43(d, 1H), 3.69 (s, 1H), 3.75-3.90 (m, 3H), 4.10 (d, 1H), 4.45 (s, 2H),6.51 (d, 1H), 7.00-7.10 (m, 3H), 7.49 (m, 2H), 7.70 (m, 1H), 8.46 (s,1H) 200 1H NMR (400 MHz, CDCl₃): δ 0.90-1.15 (m, 5H), 1.40-1.60 (m, 3H),1.60-1.85 (m, 3H), 1.95 (m, 2H), 3.20 (d, 1H), 3.55 (d, 2H), 3.68 (m,2H), 3.70-3.85 (m, 6H), 3.85-3.95 (m, 2H), 6.48 (d, 1H), 7.02 (s, 1H),7.27 (d, 2H), 7.42 (d, 2H), 7.67 (d, 1H), 8.43 (d, 1H) 236 ¹H-NMR (400MHz, CD₃OD): δ 6.87 (s, 1H), 4.19 (s, 2H), 4.05 (m, 2H), 3.82 (s, 1H),1.43-1.90 (m, 6H), 1.06-1.39 (m, 14H) 279 1H NMR (400 MHz, CDCl₃): δ0.93-1.15 (m, 4H), 1.29-1.39 (m, 1H), 1.45 (m, 1H), 1.50-1.60 (m, 2H),1.65 (m, 1H), 1.70-1.80 (d, 1H), 1.80-1.90 (d, 1H), 1.90-2.10 (m, 4H),3.05 (d, 1H), 3.20 (m, 1H), 3.27 (s, 3H), 3.30 (m, 1H), 3.36-3.53 (m,3H), 3.61-3.74 (m, 2H), 4.06 (d, 1H), 6.42 (s, 1H), 6.99-7.07 (m, 3H),7.48 (m, 2H), 7.64 (d, 1H), 8.42 (s, 1H) 295 1H NMR (400 MHz, CDCl₃): δ0.96-1.14 (m, 4H), 1.32-1.44 (m, 1H), 1.48 (m, 1H), 1.57 (m, 2H), 1.67(m, 1H), 1.76 (d, 1H), 1.83 (d, 1H), 2.30 (s, 3H), 2.98 (d, 1H), 3.40(d, 1H), 3.67 (m, 1H), 3.79 (d, 1H), 3.91 (s, 3H), 4.10 (d, 1H), 7.06(s, 1H), 7.15 (d, 2H), 7.42 (d, 2H), 7.71 (s, 1H), 7.75 (s, 1H) 302 1HNMR (400 MHz, CDCl₃): δ 0.97-1.15 (m, 4H), 1.27 (m, 1H), 1.47-1.64 (m,3H), 1.68 (m, 1H), 1.76 (d, 1H), 1.84 (d, 1H), 2.28 (s, 3H), 2.73 (s,3H), 3.31 (d, 1H), 3.52 (d, 1H), 3.71 (m, 1H), 3.85 (d, 1H), 4.14 (d,1H), 7.06 (s, 1H), 7.12 (d, 1H), 7.40 (d, 2H), 7.45 (d, 1H), 8.13 (d,1H), 8.98 (s, 1H) 311 ¹H-NMR (400 MHz, CD₃OD): δ 6.91 (s, 1H), 4.23 (d,1H), 3.94 (d, 1H), 3.62 (m, 1H), 3.55 (m, 2H), 1.96-1.52 (m, 10H), 1.45(s, 3H), 1.32 (s, 9H), 1.21 (m, 4H), 1.05 (m, 1H) 314 1H NMR (400 MHz,CDCl₃): δ 0.94-1.13 (m, 4H), 1.26 (m, 1H), 1.38 (m, 1H), 1.43 (s, 3H),1.45 (s, 3H), 1.47-1.59 (m, 2H), 1.62 (m, 1H), 1.74 (d, 1H), 1.87 (d,1H), 2.29 (s, 3H), 3.45 (m, 1H), 3.84 (d, 1H), 4.09 (d, 1H), 7.02 (s,1H), 7.12 (d, 2H), 7.42 (d, 2H) 316 ¹H-NMR (400 MHz, CD₃OD): δ 6.93 (s,1H), 4.23 (m, 1H), 3.80 (m, 1H), 2.49 (m, 1H), 2.06-1.42 (m, 10H), 1.32(s, 9H), 1.22 (d, 3H), 1.12 (m, 5H). 318 ¹H-NMR (400 MHz, CD₃OD): δ 6.97(s, 1H), 4.11 (d, 1H), 3.92 (d, 1H), 3.62 (m, 1H), 2.17 (m, 1H), 1.93(m,1H), 1.62-1.85 (m, 4H), 1.45-1.62 (m, 4H), 1.37-1.44 (m, 3H),1.27-1.37 (m, 10H), 1.11-1.27 (m, 10H) 319 ¹H-NMR (400 MHz, CD₃OD): δ6.97 (s, 1H), 4.18 (d, 1H), 3.94 (d, 1H), 3.53 (m, 1H), 2.17 (t, 1H),1.95 (m,2H), 1.70-1.86 (m, 4H), 1.58-1.69 (m, 2H), 1.46-1.58 (m, 2H),1.39-1.46 (m, 3H), 1.29-1.39 (m, 10H), 1.10-1.29 (m, 10H) 322 ¹H-NMR(400 MHz, CD₃OD): δ 6.95 (s, 1H), 4.09 (m, 1H), 3.74 (m, 1H), 2.09 (m,1H), 1.94-1.67 (m, 8H), 1.38 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 323¹H-NMR (400 MHz, CD₃OD): 8 6.87 (s, 1H), 4.24 (tert, 1H), 3.93 (d, 1H),3.62-3.82 (m, 3H), 2.08-2.21 (m, 1H), 1.88-2.04 (m, 2H), 1.56-1.87 (m,4H), 1.43-1.56 (m, 4H), 0.98-1.35 (m, 14H) 324 1H NMR (400 MHz, CDCl₃):δ 0.88-1.13 (m, 4H), 1.32 (m, 2H), 1.43 (s, 3H), 1.48-1.67 (m, 3H),1.69-1.87 (m, 4H), 1.96 (m, 1H), 2.06 (m, 1H), 2.31 (s, 3H), 3.67 (m,1H), 7.08 (s, 1H), 7.15 (d, 2H), 7.44 (d, 2H) 325 1H NMR (400 MHz,CDCl₃): δ 0.96-1.19 (m, 5H), 1.23 (s, 9H), 1.37 (m, 1H), 1.45 (m, 1H),1.61 (m, 2H), 1.64-1.81 (m, 4H), 1.83 (m, 1H), 2.22 (m, 1H), 3.37(m,1H), 3.57-3.78 (m, 4H), 3.89 (d, 1H), 3.98 (d, 1H), 6.79 (s, 1H) 326¹H-NMR (400 MHz, CD₃OD): δ 6.78 (s, 1H), 4.07 (m, 1H), 3.53 (m, 2H),2.26 (m, 1H), 1.96-1.38 (m, 14H), 1.30 (s, 9H), 1.14 (m, 5H). 328 ¹H-NMR(400 MHz, CD₃OD): δ 6.87 (s, 1H), 4.14 (tert, 1H), 3.92 (tert, 1H), 3.77(d, 1H), 3.70 (t, 2H), 2.32 (m, 1H), 1.82-1.99 (m, 2H), 1.71-1.82 (m,2H), 1.66 (m, 1H), 1.41-1.59 (m, 5H), 1.03-1.34 (m, 14H) 334 ¹H-NMR (400MHz, CD₃OD): δ 6.95 (s, 1H), 4.08 (m, 1H), 3.74 (m, 1H), 2.18 (m, 1H),1.94-1.67 (m, 8H), 1.42 (m, 1H), 1.33 (s, 9H), 1.17 (m, 5H) 336 1H NMR(400 MHz, CD₃OD): δ 1.09-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.85 (m, 5H),1.89-2.10 (m, 3H), 3.56-3.61 (m, 1H), 3.93-4.00 (m, 1H), 4.00-4.10 (m,1H), 4.12-4.22 (m, 2H), 6.99 (s, 1H) 337 1H NMR (400 MHz, CD₃OD): δ1.07-1.31 (m, 8H), 1.32 (s, 9H), 1.45-1.60 (m, 2H), 1.63-1.85 (m, 4H),1.87-1.98 (m, 1H), 2.02-2.11 (m, 1H), 3.60-3.66 (m, 1H), 3.93-4.03 (m,2H), 4.15 (d, 1H), 4.26-4.35 (m, 1H), 6.94 (s, 1H) 340 ¹H-NMR (400 MHz,CD₃OD): δ 6.81 (s, 1H), 3.96 (br, 1H), 3.48 (m, 1H), 2.06 (m, 3H), 1.84(m, 3H), 1.70 (br, 2H), 1.46 (m, 1H), 1.37 (m, 1H), 1.31 (s, 9H), 1.16(m, 5H) 341 ¹H-NMR (400 MHz, CD₃OD): δ 6.81 (s, 1H), 4.00 (br, 1H), 3.53(t, 2H), 2.27 (br, 1H), 1.97 (m, 3H), 1.82-1.64 (m, 7H), 1.58 (m, 2H),1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H) 343 ¹H-NMR (400 MHz, CD₃OD): δ6.85 (s, 1H), 3.92 (br, 1H), 3.67 (m, 2H), 2.41 (br, 1H), 2.15 (m, 1H),1.97 (m, 2H), 1.78 (m, 7H), 1.37 (m, 2H), 1.31 (s, 9H), 1.14 (m, 5H).

BIOLOGICAL EXAMPLES Biological Example 1 Anti-Hepatitis C Activity

Compounds can exhibit anti-hepatitis C activity by inhibiting HCVpolymerase, by inhibiting other enzymes needed in the replication cycle,or by other pathways. A number of assays have been published to assessthese activities. A general method that assesses the gross increase ofHCV virus in culture was disclosed in U.S. Pat. No. 5,738,985 to Mileset al. In vitro assays have been reported in Ferrari et al. Jnl. ofVir., 73:1649-1654, 1999; Ishii et al., Hepatology, 29:1227-1235, 1999;Lohmann et al., Jnl of Bio. Chem., 274:10807-10815, 1999; and Yamashitaet al., Jnl. of Bio. Chem., 273:15479-15486, 1998.

WO 97/12033, filed on Sep. 27, 1996, by Emory University, listing C.Hagedorn and A. Reinoldus as inventors, which claims priority to U.S.Provisional Patent Application Ser. No. 60/004,383, filed on September1995, described an HCV polymerase assay that can be used to evaluate theactivity of the of the compounds described herein. Another HCVpolymerase assay has been reported by Bartholomeusz, et al., Hepatitis CVirus (HCV) RNA polymerase assay using cloned HCV non-structuralproteins; Antiviral Therapy 1996:1 (Supp 4) 18-24.

Screens that measure reductions in kinase activity from HCV drugs weredisclosed in U.S. Pat. No. 6,030,785, to Katze et al., U.S. Pat. No.6,228,576, Delvecchio, and U.S. Pat. No. 5,759,795 to Jubin et al.Screens that measure the protease inhibiting activity of proposed HCVdrugs were disclosed in U.S. Pat. No. 5,861,267 to Su et al., U.S. Pat.No. 5,739,002 to De Francesco et al., and U.S. Pat. No. 5,597,691 toHoughton et al.

Biological Example 2 Replicon Assay

A cell line, ET (Huh-lucubineo-ET) was used for screening of compoundsfor inhibiting HCV RNA dependent RNA polymerase. The ET cell line wasstably transfected with RNA transcripts harboring aI₃₈₉luc-ubi-neo/NS3-3′/ET; replicon with fireflyluciferase-ubiquitin-neomycin phosphotransferase fusion protein andEMCV-IRES driven NS3-5B polyprotein containing the cell culture adaptivemutations (E1202G; T12801; K1846T) (Krieger at al, 2001 andunpublished). The ET cells were grown in DMEM (Dulbeco's ModifiedEagle's Medium), supplemented with 10% fetal calf serum, 2 mM Glutamine,Penicillin (100 IU/mL)/Streptomycin (100 μg/mL), 1× nonessential aminoacids, and 250 μg/mL G418 (“Geneticin”). Reagents were all availablethrough Life Technologies (Bethesda, Md.). The cells were plated at0.5-1.0×10⁴ cells/well in the 96 well plates and incubated for 24 hrsbefore adding test compound. The compounds were added to the cells toachieve a final concentration of 0.1 nM to 50 μM and a final DMSO(dimethylsulfoxide) concentration of 0.5%. Luciferase activity wasmeasured 48 hours later by adding a lysis buffer and the substrate(Catalog number Glo-lysis buffer E2661 and Bright-Glo luciferase systemE2620 Promega, Madison, Wis.). Cells should not be too confluent duringthe assay. Percent inhibition of replication data was plotted relativeto no compound control. To determine the EC₅₀ (effective concentrationat which 50% of the maximum inhibition was observed), a 10 point, 3-foldserial dilution for each compound was used, which spans a concentrationrange of 1000 fold. EC₅₀ values were calculated by fitting % inhibitionat each concentration to the following equation:% inhibition=100%/[(EC₅₀ /[I])^(b)+1]where b was Hill's coefficient.

In some aspects, certain compounds of Formula (I), exhibited EC₅₀ ofequal to or less than 50 μM when tested according to the assay ofExample 2. In other aspects the EC₅₀ was equal to or less than 10 μM. Instill other aspects the EC₅₀ was equal to or less than 1 μM.

Biological Example 3 Cloning and Expression of Recombinant HCV-NS5b

The coding sequence of NS5b protein was cloned by PCR frompFKI₃₈₉Iuc/NS3-3′/ET as described by Lohmann, V., et al. (1999) Science285, 110-113 using the primers shown on page 266 of WO 2005/012288.

The cloned fragment was missing the C terminus 21 amino acidsubstituents. The cloned fragment was inserted into an IPTG-inducible(isopropyl-β-D-thiogalactopyranoside) expression plasmid that providesan epitope tag (His)6 at the carboxy terminus of the protein.

The recombinant enzyme was expressed in XL-1 cells and after inductionof expression, the protein was purified using affinity chromatography ona nickel-NTA (nitrilotriacetic acid) column. Storage conditions were 10mM Tris-HCl pH 7.5, 50 mM NaCl, 0.1 mM EDTA (ethylenediaminetetraaceticacid), 1 mM DTT (dithiothreotol), and 20% glycerol at −20° C.

Biological Example 4 HCV-NS5b Enzyme Assay Using Heteropolymer Substrate

The polymerase activity was assayed by measuring incorporation ofradiolabeled UTP into a RNA product using a biotinylated,heteropolymeric template, which included a portion of the HCV genome.Typically, the assay mixture (50 μL) contained 10 mM Tris-HCl (pH 7.5),5 mM MgCl₂, 0.2 mM EDTA, 10 mM KCl, 1 unit/μL RNAsin, 1 mM DTT, 10 μMeach of NTP (nucleoside triphosphate), including [³H]-UTP (uridinetriphosphate), and 10 ng/μL heteropolymeric template. Test compoundswere initially dissolved in 100% DMSO and further diluted in aqueousbuffer containing 5% DMSO. Typically, compounds were tested atconcentrations between 1 nM and 100 μM. Reactions were started withaddition of enzyme and allowed to continue at 37° C. for 2 hours.Reactions were quenched with 8 μL of 100 mM EDTA and reaction mixtures(30 μL) were transferred to streptavidin-coated scintillation proximitymicrotiter plates (Flash Plates) and incubated at room temperatureovernight. Incorporation of radioactivity was determined byscintillation counting.

Biological Example 5 HCV-NS5b Enzyme Assay Using Homopolymer Substrate

The polymerase activity was assayed by measuring incorporation ofradiolabeled UTP into a RNA product using a biotinylated, homopolymerictemplate. The template was formed by annealing adenosine homopolymer touridine 20-mer capped with a 5′-biotin group (biotin-U²⁰) in the ratioof 1:4. Typically, the assay mixture (50 μL) contained 25 mM Tris-HCl(pH 7.5), 40 mM KCl, 0.3 mM MgCl₂, 0.05 mM EDTA, 0.2 unit/μL SuperaseRNAse Inhibitor, 5 mM DTT, 30 μM UTP (Uridine triphosphate), including[³H]-UTP (uridine triphosphate) at 0.4 μCi/μL with final concentrationof 1 μM, and 50 nM of homopolymeric template. Test compounds wereinitially dissolved in 100% DMSO and further diluted in aqueous buffercontaining 5% DMSO. Typically, compounds were tested at concentrationsbetween 2 nM and 50 μM. Reactions were started with addition of enzymeand allowed to continue at 30° C. for 90 minutes. Reactions werequenched with 8 μL of 100 mM EDTA and reaction mixtures (30 μL) weretransferred to streptavidin-coated scintillation proximity microtiterplates (Flash Plates) and incubated at room temperature overnight.Incorporation of radioactivity was determined by scintillation counting.

Inhibitor IC₅₀ values were determined by adding test compound as tenpoint, two-fold serial dilutions in 100% DMSO with a final reactionconcentration of 5%. IC₅₀ values were calculated by plotting the %inhibition against compound concentration and fitting the data to aconstrained four parameter sigmoidal curve, equivalent to the “fourparameter logistic equation”, where Bottom was the minimum Y value, Topwas the maximum Y value, and Hillslope was the slope of the linearportion of the semi-log curve. Top and Bottom were constrained to valuesof 0% and 100%, respectively. These analyses were performed usingGraphpad Prism v.4.0 (Graphpad Software, Inc.) in conjunction with DSAccord for EXCEL 6.0 (Accelrys, Microsoft Corp.).

Biological Example 6

The polymerase activity was also assayed by measuring incorporation ofradiolabeled GTP into an RNA product using a biotinylated oligoGl3primer with a polycytidylic acid RNA template. Typically, the assaymixture (40 μL) contains 50 mM HEPES (pH 7.3), 2.5 mM magnesium acetate,2 mM sodium chloride, 37.5 mM potassium acetate, 5 mM DTT, 0.4 U/mLRNasin, 2.5% glycerol, 3 nM NS5B, 20 nM polyC RNA template, 20 nMbiotin-oligoGl3 primer, and 0.2 μM tritiated guanosine triphosphate.Test compounds were initially dissolved and diluted in 100% DMSO andfurther diluted into aqueous buffer, producing a final concentration of5% DMSO. Typically, compounds were tested at concentrations between 0.2nM and 10 μM. Reactions were started with addition of tritiatedguanosine triphosphate and allowed to continue at 30° C. for 2 hours.Reactions were quenched with 100 μL stop buffer containing 10 mM EDTAand 1 μg/mL streptavidin-coated scintillation proximity beads. Reactionplates were incubated at 4° C. for 10 hours and then incorporation ofradioactivity was determined by scintillation counting.

Compounds in Table 1 supra have been tested in the polymerase assay ofBiological Example 1 and the IC₅₀ values for each compound were providedin Table 3 infra. Most of the compounds of Table 1 exhibit an IC₅₀ of 1μM or less or an IC₅₀ of 500 nM or less in the replicon assay ofBiological Example 2 provided herein. For example, the compounds ofExample numbers 2, 3, 5, 7, 8, 10, 11, 19, 35, 69, 74, 75, 76, 77, 78,79, 80, 81, 82, 84, 85, 86, 87, 88, 89, 90, 91, 91, 92, 93, 94, 95, 96,99, 118, 119, 120, 121, 122, 123, 125, 126, 127, 130, 135, 137, 138,140, 141, 143, 145, 146, 147, 148, 149, 150, 151, 152, 154, 155, 156,157, 158, 160, 161, 162, 163, 164, 165, 167, 168, 169, 170, 171, 172,173, 176, 177, 179, 180, 182, 183, 184, 185, 186, 187, 188, 189, 190,191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 208,212, 213, 216, 217, 218, 219, 222, 224, 225, 226, 227, 228, 229, 231,232, 233, 234, 235, 236, 238, 239, 240, 241, 243, 244, 246, 247, 248,250, 251, 253, 256, 257, 258, 272, 273, 274, 275, 276, 277, 278, 279,280, 281, 283, 284, 285, 286, 287, 288, 289, 290, 291, 292, 295, 296,297, 298, 299, 301, 302, 303, 304, 305, 307, 308, 310, 311, 312, 313,314, 315, 316, 318, 319, 320, 321, 322, 323, 325, 327, 328, 329, 330,332, 334, 336, 337, 339, 340, 341, 342, 343 exhibit an IC₅₀ of 100 nM orless in the replicon assay of Biological Example 2. The compounds ofExample numbers 1, 4, 6, 12, 13, 17, 18, 24, 26, 27, 29, 31, 36, 37, 38,39, 40, 42, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 58, 59, 60,61, 62, 63, 64, 65, 66, 67, 70, 71, 72, 73, 83, 97, 98, 100, 101, 102,103, 104, 105, 106, 107, 108, 109, 113, 114, 115, 116, 124, 128, 129,131, 136, 139, 142, 144, 153, 159, 178, 181, 204, 205, 206, 207, 209,211, 214, 215, 220, 221, 223, 230, 237, 242, 245, 249, 252, 254, 255,259, 260, 262, 267, 282, 293, 294, 300, 206, 309, 317, 324, 326, 331,333, 335, 338 exhibit an IC₅₀ between 100 nM and 5.0 uM in the repliconassay of Biological Example 2. The compounds of Example numbers 9, 15,16, 20, 21, 22, 23, 25, 28, 30, 32, 33, 34, 41, 47, 57, 110, 111, 112,117, 132, 166, 174, 175, 210, 271 exhibit an IC₅₀ of 5.0 μM or more inthe replicon assay of Biological Example 2.

TABLE 3 NS5B- enzyme3 Retention (uM) MS [M + H⁺] time (min) HPLC method1 0.1815 370.4 12.36 A 2 0.035 448.3 13.02 A 3 0.004 448.3 13.03 A 40.073 384.4 12.76 A 5 0.052 427.5 13.06 A 6 — 370.1 12.4 A 7 0.006 462.213.72 A 8 0.001 434.3 8.45 A 9 0.08 398.2 11.64 A 10 0.003 464.3 7.96 A11 0.008 461.9 12.25 A 12 0.045 400.5 10.48/11.76 A 13 0.079 386.1 12.14A 14 3.651 485.6 14.11 A 15 0.0735 385.3 6.12 A 16 0.4205 489.3 12.73 A17 0.024 475.2 12.48 A 18 0.002 539.6 14.19 A 19 0.015 388.6 14.3 A 200.128 517.6 12.55/13.80 A 21 0.97 533.6 13.11 A 22 0.02 533.6 13.45 A 230.245 399.5 5.89 A 24 0.0445 503.6 13.46 A 25 0.173 503.4 12.66 A 260.067 463.3 12.13 A 27 0.022 539.3 13.7 A 28 0.226 399.5 7.01 A 29 0.001599.3 12.76 A 30 0.003 569.3 13.09 A 31 0.047 519.6 14.34 A 32 0.241544.6 13.79 A 33 0.038 587.3 12.8 A 34 1.05 388.6 14.34 A 35 0.0095388.4 14.35 A 36 0.058 546.6 14.69 A 37 0.072 492.6 12.8 A 38 0.065505.6 13.75 A 39 0.051 553.4 14.19 A 40 0.013 543.3 13.87 A 41 0.218521.3 11.71 A 42 0.148 517.6 13.73 A 43 553.6 15.49 A 44 553.6 12.91 A45 4.9 505.6 13.55 A 46 0.063 531.6 14.33 A 47 0.088 492.3 6.52 A 480.187 402.3 13.73 A 49 0.015 539.17 4.16 C 50 0.007 582.17 3.69 C 510.011 617.18 4.57 C 52 0.015 525.15 4.1 C 53 0.024 609.13 7.56 B 540.018 593.14 6.97 B 55 0.071 609.14 4.22 C 56 0.0071 553.18 4.4 C 570.26 578.18 8.23 B 58 0.088 539.17 6 B 59 0.039 609.13 6.75 B 60 0.009601.18 4.73 C 61 0.003 578.18 8.98 B 62 0.011 529.16 7.84 B 63 0.042617.19 9.78 B 64 0.031 578.17 9.18 B 65 0.045 601.18 7.23 B 66 0.049611.13 4.39 C 67 0.1835 402.3 13.48 A 68 593.14 6.77 B 69 0.002 597.416.51 A 70 0.067 402.5 15.7 A 71 0.052 398.5 16.1 A 72 0.064 412.6 16.77A 73 0.021 418.5 16.91 A 74 0.012 581.19 8.44 B 75 0.008 623.24 2.28 D76 0.004 595.6 17.16 A 77 0.003 625.6 17.66 A 78 0.005 599.2 7.91 B 790.004 627.18 17.35 A 80 0.006 657.24 9.57 B 81 0.009 612.23 4.74 B 820.006 609.22 7.11 B 83 0.003 629.21 7.16 B 84 0.004 609.22 16.76 A 850.002 583.5 16.78 A 86 0.006 585.18 7.1 B 87 0.005 639.23 17.73 A 880.002133 610.3 7.08 A 89 0.003 652.23 7.62 B 90 0.004 625.22 7.95 B 910.012 637.25 17.92 A 92 0.004 623.5 8.17 B 93 0.004 625.22 7.65 B 940.002 639.5 17.13 A 95 0.005 645.4 17.27 A 96 623.4 17.53 A 97 0.027550.3 11.24 A 98 0.003 582.3 9.34 A 99 0.002 597.3 10.73 A 100 0.004567.3 13.4 A 101 0.011 591.3 11.52 A 102 0.0045 585.3 10.83 A 103 0.002555.3 11.42 A 104 0.021 543.3 11.85 A 105 0.002 581.3 14.04 A 106 0.014591.3 11.98 A 107 <0.001 555.3 11.66 A 108 0.037 526.3 9.94 A 109 0.03543.3 11.57 A 110 0.183 573.2] 12.89 A 111 0.243 593.2 13.18 A 112 0.173666.4 12.61 A 113 0.044 440.6 16.03 A 114 0.09 414.5 12.96 A 115 0.004506.3 11.8 A 116 0.064 428.6 13.88 A 117 0.739 452.5 13.93 A 118 0.002609.4 12.09 A 119 0.009 609.4 12.12 A 120 0.006 613.3 10.87 A 121 0.007613.3 10.87 A 122 0.002 625.4 9.33 A 123 0.002 611.3 8.46 A 124 0.004611.3 8.46 A 125 0.018 621.4 12.74 A 126 0.011 637.3 13.87 A 127 0.003608.3 12.96 A 128 0.009 625.3 9.86, 10.06 A 129 0.096 409.2 12.3 A 1300.001 609.3 14.24 A 131 0.261 609.3 14.27 A 132 0.108 610.3 7.09 A 133418.2 14.01 A 134 398.5 13.56 A 135 0.002333 595.3 13.58 A 136 0.26595.3 13.61 A 137 0.0015 624.3 7.15 A 138 0.001 638.3 7.21 A 139 0.001640.3 7.05 A 140 0.001 624.3 7.2 A 141 0.002 610.3 7.02 A 142 0.002624.3 7.21 A 143 0.0019 638.3 7.14 A 144 0.002 610.3 6.98 A 145 0.001624.3 7.19 A 146 0.002 710.4 2.23 D 147 0.001 652.4 2.34 D 148 0.002638.3 2.17/ D 149 0.003 738.4 2.40/ D 150 0.004 638.3 2.21/ D 151 0.003724.4 2.40/ D 152 0.003 666.4 2.31/ D 153 0.004 738.4 2.43/ D 154 0.003623.3 2.28/ D 155 0.003 652.4 2.15 D 156 0.001 638.3 2.15 D 157 0.001650.4 2.13 D 158 0.002 623.3 2.35 D 159 0.003 724.4 2.22 D 160 0.001652.4 2.16 D 161 0.001 740.4 2.18 D 162 0.002 724.4 2.38 D 163 0.001638.3 2.12 D 164 0.001 623.3 2.27 D 165 0.002 710.4 2.2 D 166 0.982543.5 15.74 A 167 0.0035 639.3 14.32 A 168 3.8165 615.5 14.95 A 1690.003 629.2 15.57 A 170 0.004 643.2 16.03 A 171 0.002 639.3 14.02 A 1720.0012 609.6 13.8 A 173 0.001 623.6 15 A 174 5.113 493.2 15.41 A 175 >10389.2 6.89 A 176 1.41285 571.5 16.35 A 177 0.002 597.2 14.33 A 178 0.001602.2 14.89 A 179 0.001 609.2 14.81 A 180 <0.0002 623.2 14.74 A 1810.003 376.4 14.22 182 0.002 545.3 6.78 A 183 0.0018 623.5 15.31 A 1840.0017 611.2 13.24 A 185 0.001 627.2 14.41 A 186 0.001 643.2 13.57 A 1870.001 625.2 13.96 A 188 0.001 638.8 14.04 A 189 0.001 628.8 13.5 A 1900.001 559.4 15.28 A 191 0.001 560.4 15.33 A 192 0.003 530.1 14.74 A 1930.001 533.4 14.21 A 194 0.002 625.2 13.26 A 195 0.003 643.2 14.24 A 1960.001 655.3 13.87 A 197 0.0046 639.2 14.58 A 198 0.001 651.3 14.21 A 1990.002 645.2 14.63 A 200 0.001 659.3 14.75 A 201 643.3 15.55 A 202 0.001728.3 2.21 D 203 0.001 645.2 2.43 D 204 0.002 633.2 2.32 D 205 0.004638.1 2.38 D 206 0.001 604.1 2.13 D 207 603.1 2.21 D 208 0.0014 701.22.29 D 209 0.001 592.1 2.14 D 210 0.003 652.1 1.79 D 211 0.002 606.12.36 D 212 0.002 674.2 2.38 D 213 0.001 627.1 2.25 D 214 0.001 603.12.16 D 215 0.002 592.2 2.34 D 216 0.001 637.3 13.63 A 217 0.001 623.212.73 A 218 0.001 667.3 15.39 A 219 623.2 14.75 A 220 0.015 374.2 14.17221 0.019 495.1 14.79 A 222 0.002 606.2 2.14 D 223 0.009 613.2 16.14 A224 701.3 7.4 A 225 0.001 625.2 13.72 A 226 0.009 659.1 15.15 A 2270.001 671.2 14.94 A 228 641.3 12.97 A 229 0.001 657.2 14.1 A 230 0.006598.1 15.77 A 231 0.001 628.2 15.91 A 232 0.001 613.2 13.77 A 233 0.002642.2 16.26 A 234 0.001 642.1 16.2 A 235 627.2 14.99 A 236 0.003 390.113.86 A 237 0.042 403.2 1.16 E 238 0.002 554.2 7.65 B 239 0.002 547.27.8 B 240 534.2 7.62 B 241 0.001 519.2 6.88 B 242 0.005 563.1 8.07 B 2430.002 547.2 7.75 B 244 0.002 564.2 7.75 B 245 0.005 493.2 7.3 B 2460.004 577.2 7.75 B 247 0.002 519.2 6.57 B 248 0.002 547.2 6.82 B 2490.019 613.2 8.03 B 250 0.0055 597.2 8.06 B 251 0.004 565.2 7.73 B 2520.002 586.2 7.22 B 253 0.002 586.2 7.13 B 254 0.015 533.2 7.49 B 2550.005 547.2 6.57 B 256 0.001 557.2 8.07 B 257 0.002 559.2 7.74 B 2580.007 559.2 7.54 B 259 0.007 554.2 15.23 A 260 0.008 547.1 14.54 A 2610.199 540.1 2.44 D 262 0.025 558.1 2.14 D 263 0.108 489.2 2.39 D 2640.538 503.2 2.43 D 265 0.601 481.2 2.49 D 266 0.142 578.2 2.39 D 2670.064 510.1 2.2 D 268 0.62 489.2 2.36 D 269 0.33 489.2 2.37 D 270 0.019518.2 2.34 D 271 2.47 482.2 2.12 D 272 0.001 609.2 14.15 A 273 0.001641.4 12.87 A 274 0.001 657.2 14 A 275 0.002 547.4 14.31 A 276 0.002607.5 15.04 A 277 0.002 589.2 14.81 A 278 0.001 657.3 14.46 A 279 0.0011657.2 13.52 A 280 0.001 631.2 13.51 A 281 0.003 565.1 15.58 A 282 0.031597.1 16.45 A 283 0.004 577.2 15.44 A 284 0.003 563.4 13.81 A 285 0.002641.3 15.2 A 286 0.001 649.2 14.09 A 287 0.001 631.2 13.53 A 288 0.002643.3 12.21 A 289 0.001 637.5 13.42 A 290 0.002 418.2 14.92 A 291 0.008404.5 14.02 292 0.0023 656.8 15.79 A 293 0.005 420.1 13.56 A 294 0.007517.3 13.08 A 295 0.004 543.2 13.03 A 296 0.005 557.3 13.45 A 297 0.001543.2 12.33 A 298 0.001 557.2 12.33 A 299 0.005 448.5 13.07 300 0.031564.1 14.79 A 301 0.004 585.2 14.32 A 302 0.003 554.2 13.74 A 303 0.004596.2 15.55 A 304 0.005 568.2 14.3 A 305 0.004 568.2 14.05 A 306 0.0053510.1 13.32 307 0.006 477.2 7.32, 7.64 A 308 0.014 390.5 13.82 309 0.054467.1 17.57 A 310 0.004 489.2 7.35, 7.85 A 311 0.002 461.8 12.88 A 3120.002 443.2 14.94 A 313 0.0315 404.2 13.55 A 314 0.006 427.8 13.88 A 3150.006 448.1 14.44 A 316 0.003 432.3 14.19 A 317 0.0241 414.2 12.27 A 3180.014 490.3 14.7 A 319 0.004 490.2 14.04 A 320 0.006 476.2 14.29 A 3210.002 476.2 13.52 A 322 0.006 404.2 13.07 A 323 0.003 448.3 12.86 A 3240.085 427.9 12.45 A 325 0.006 459.8 14.87 A 326 0.8815 446.3 13.68 A 3270.004 478.6 12.57, 12.72 A 328 0.006 448.3 13.51 A 329 0.005 420.5 12.66A 330 0.003 478.3 11.66, 11.93 A 331 0.008 464.3 7.92 A 332 0.012 434.28.32 A 333 0.01 478.3 11.7 A 334 0.003 403.8 13.5 A 335 0.024 402.1 A336 0.003 448.3 10.28 A 337 0.002 448.2 10.89 A 338 0.031 462.3 [M − H⁺]9.95 A 339 0.008 446 13.67 A 340 0.008 403.0 7.21 A 344 0.005 446 13.17A 342 0.018 432 13.51 A 343 0.001 432 13.29 A

What is claimed is:
 1. A method of treating a disorder or a diseasecaused by or associated with HCV infection in a subject having saiddisorder or disease, wherein the method comprises administering to thesubject a therapeutically effective amount of the compound of Formula(I):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; nis 0 or 1, wherein m+n is 1, 2 or 3; R₁ is C₃-C₁₀alkynyl or phenyl,which phenyl is substituted with 0, 1, 2, or 3 substituents which areindependently selected from the group consisting of halogen, hydroxy,cyano, C₁-C₄alkyl, haloC₁-C₄alkyl and C₁-C₄alkoxy, and which alkynyl isoptionally substituted with a C₃-C₇cycloalkyl substituent, whichcycloalkyl is optionally substituted with 1 or 2 independently selectedC₁-C₄alkyl groups; R₂ is CO₂H or C(O)N(H)S(O)₂CH₃; R₃ is C₃-C₇cycloalkylwhich is substituted with 0, 1, 2 or 3 halogen atoms; R_(3a) represents0, 1, 2, 3 or 4 residues independently selected at each occurrence fromthe group consisting of hydroxy, amino, cyano, halogen, C₁-C₆alkyl, andC₁-C₆alkoxy, wherein each alkyl or alkoxy substituent is substitutedwith 0, 1, or 2 substituents independently selected from hydroxy, cyano,C₁-C₄alkoxy, C₁-C₄alkylsulfone, N(R_(3b))₂, C(O)N(R_(3b)), heterocyclehaving 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, Oand S and 5 or 6 member heteroaryl; or two geminal R_(3a) substituents,taken in combination form a spirocyclic 3 to 6 member cycloalkyl orheterocycle; R_(3b) is independently selected at each occurrence fromhydrogen, C₁-C₄alkyl, C₁-C₄alkoxyC₁-C₄alkyl and C₁-C₄alkanoyl; orN(R_(3b))₂, taken in combination, form a 4 to 6 member heterocyclehaving 0 or 1 additional ring heteroatoms selected from N, O and S; X isO, N-L-R₄ or CR₅R₆; L is a bond, S(O)₂ or C(O); R₄ is C₁-C₆alkyl orC₃-C₇cycloalkyl each of which is substituted with 0, 1, or 2 hydroxy and0 or 1 substituents selected from cyano, S(O)₂—C₁-C₄alkyl, CO₂H orNR_(4a)R_(4b) or phenyl; R₄ is naphthyl or phenyl, which phenyl issubstituted with 0, 1, 2, or 3 substituents independently selected formthe group consisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl,C₁-C₆alkoxy, haloC₁-C₆alkoxy, amino, hydroxy, mono- anddi-C₁-C₆alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₆alkyl-OC(O)NH—, C₁-C₄alkyl-C(O)NH—, —C(O)NR_(4a)R_(4b), phenyl,phenoxy, heteroaryl having one or two ring nitrogen atoms and having 0,1, or 2 C₁-C₄alkyl substituents, or two substituents combine to form afused heterocyclic ring, which heterocycle has 5, 6 or 7 ring atoms, 1or 2 ring heteroatoms selected from N, O and S and which heterocycle issubstituted with 0, 1 or 2 substituents independently selected fromC₁-C₆alkyl; or R₄ is a 5 or 6 member heteroaryl having 1 to 3heteroatoms selected from N, O and S, which heteroaryl is substitutedwith 0, 1, or 2 substituents independently selected from the groupconsisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl, C₁-C₆alkoxy,haloC₁-C₆alkoxy, hydroxy, NR_(4a)R_(4b), hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₁-C₆alkyl-OC(O)NH—, C₃-C₇cycloalkyl,C₅-C₇cycloalkenyl, phenyl, 5 or 6 membered heteroaryl having 1 or 2 ringheteroatoms selected from N, O and S, and saturated or partiallyunsaturated monocyclic or bicyclic heterocycle which heterocycle has 1or 2 ring N, O or S atoms, 5 to 7 ring atoms in each ring and issubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of halogen, C₁-C₆alkyl, C₁-C₆alkanoyl,C₁-C₆alkoxyC(O)N(H)—, —C₁-C₆alkoxyC(O)N(H)CH₂—, aminoC₁-C₄alkyl,C₁-C₄alkoxyC₁-C₄alkyl and NR_(4a)R_(4b), and wherein the phenyl orheteroaryl substituent is unsubstituted or substituted with 1 or 2independently selected substituents selected from halogen, CO₂H, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, CH₂NR_(4a)R_(4b) and C(O)NR_(4a)R_(4b); or R₄is a saturated heterocycle having 1 ring nitrogen and 0 or 1 additionalring heteroatom selected from N, O and S, which heterocyclic ring issubstituted with 0, 1, or 2 substituents independently selected from thegroup consisting of C₁-C₆alkyl, CO₂C₁-C₆alkyl and CO₂benzyl; R_(4a) isindependently selected at each occurrence from the group consisting ofhydrogen and C₁-C₆alkyl, wherein the alkyl substituent is unsubstitutedor substituted with hydroxy, C₁-C₄alkoxy, amino or mono- anddi-C₁-C₄alkylamino; R_(4b) is independently selected at each occurrencefrom the group consisting of hydrogen, C₁-C₆alkyl and C₁-C₄alkanoyl,wherein the alkyl substituent is unsubstituted or substituted withhydroxy, C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino; orNR_(4a)R_(4b), taken in combination, form a heterocyclic ring having onering nitrogen atom and 0 or 1 additional ring heteroatom selected fromN, O and S, which heterocyclic ring is substituted with 0, 1, 2 or 3substituents independently selected from the group consisting ofhalogen, hydroxy, amino, C₁-C₄alkyl, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxyC₁-C₄alkyl, and mono- anddi-C₁-C₄alkylamino; R₅ is absent or is selected from the groupconsisting of hydrogen and C₁-C₆alkyl; R₆ is oxo, hydrogen, hydroxy,amino, N(H)-J-R₇; J is absent, C(O) or S(O)₂; and R₇ is C₁-C₆alkyl,phenyl or benzyl, each of is optionally substituted with C₁-C₆alkyl,C₁-C₆alkoxy, halogen, phenyl or phenoxy.
 2. The method of claim 1,wherein the compound is a compound of formula II, or a pharmaceuticallyacceptable salt thereof:

wherein Z is CH or N; R₈ is selected from hydrogen, CO₂H, C₁-C₄alkyl,C-C₄alkoxy, cyano and halogen; R₉ is selected from C₁-C₆alkyl,C₁-C₆alkoxy, phenyl, NR_(9a)R_(9b), N(H)—C(O)-O—C₁-C₄alkyl, andheterocycle, wherein the heterocycle has one or two rings, each ringhaving 5, 6, or 7 ring atoms, one ring nitrogen atom and 0 or 1additional ring heteroatom selected from N, O and S, and wherein theheterocycle is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, hydroxy,amino, C₁-C₄alkyl, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄alkoxyC₁-C₄alkyl, and mono- and di-C₁-C₄alkylaminoR_(9a) is selected from the group consisting of hydrogen and C₁-C₆alkyl,wherein the alkyl substituent is unsubstituted or substituted withhydroxy, C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino; and R_(9b)is selected from the group consisting of hydrogen, C₁-C₆alkyl andC₁-C₄alkanoyl, wherein the alkyl substituent is unsubstituted orsubstituted with hydroxy, C₁-C₄alkoxy, amino or mono- anddi-C₁-C₄alkylamino.
 3. The method of claim 1, wherein the compound is acompound of formula III, or a pharmaceutically acceptable salt thereof:

wherein R₆ is hydrogen, hydroxy, amino or N(H)-J-R₇; J is C(O) or S(O)₂;R₇ is (a) C₁-C₄alkyl optionally substituted with phenyl or phenoxy, or(b) phenyl optionally substituted with C₁-C₄alkyl, halogen orC₁-C₄alkoxy; R₁₀ is selected from hydrogen and C₁-C₆alkyl which alkyl issubstituted with 0, 1, or 2 hydroxy and 0 or 1 substituents selectedfrom cyano, SO₂CH₃, methoxy, ethoxy, N(R_(10a))₂ and C(O)(NR_(10a))₂;R_(10a) is selected at each occurrence from the group consisting ofhydrogen and C₁-C₄alkyl which is substituted with 0 or 1 substituentsselected from hydroxy, methoxy and ethoxy; R₁₁ is selected from thegroup consisting of hydrogen, fluoro, cyano, hydroxy and C₁-C₄alkyl. 4.The method of claim 1, wherein the compound is a compound of formula IV,or a pharmaceutically acceptable salt thereof:

wherein R₁₀ and R₁₁ are independently selected from hydrogen andC₁-C₆alkyl which alkyl is substituted with 0, 1, or 2 hydroxy and 0 or 1substituents selected from SO₂CH₃, cyano, methoxy, ethoxy, N(R_(10a))₂and C(O)N(R_(10a))₂; R_(10a) is selected at each occurrence from thegroup consisting of hydrogen and C₁-C₄alkyl which is substituted with 0or 1 substituents selected from hydroxy, methoxy and ethoxy, orN(R_(10a))₂, taken in combination forms a 4 to 6 member heterocyclicring; R₁₂ is selected from the group consisting of hydrogen andC₁-C₄alkyl.
 5. The method of claim 1, wherein R₁ is tert-butylethynyl,phenyl, or phenyl para-substituted with F, Cl, or Me.
 6. The method ofclaim 5, wherein R₁ is tert-butylethynyl.
 7. The method of claim 1,wherein R₂ is CO₂H.
 8. The method of claim 1, wherein R₃ is cyclohexyl.9. The method of claim 1, wherein the disorder or the disease isselected from HCV infection, liver cirrhosis, chronic liver disease,hepatocellular carcinoma, cryoglobulinaemia, non-Hodgkin's lymphoma,liver fibrosis and a suppressed innate intracellular immune response.10. The method of claim 1, wherein the compound is selected from thegroup consisting of:3-((S)-2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid;3-(3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;5-(4-Chloro-phenyl)-3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-4-(6-dipropylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((R)-2-methyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((2S,5R)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-diethylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(4-methoxy-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-methoxy-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(1-methyl-1H-pyrazole-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-p-tolyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((4S,5R)-5-Cyclohexyl-3,4-dimethyl-2-oxo-imidazolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;5-(4-Chloro-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(3-methanesulfonyl-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-5-Cyclohexyl-2-[(2-methoxy-ethylamino)-methyl]-3-oxo-morpholin-4-yl}-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(4-Cyclohexyl-2-oxo-[1,3]oxazinan-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2-morpholin-4-ylmethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((2S,5R)-2-Cyanomethyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2,2-dimethyl-3-oxo-morpholin-4-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-3-methyl-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-((R)-3-Cyclohexyl-5-oxo-1,9-dioxa-4-aza-spiro[5.5]undec-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2-hydroxymethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[6-Cyclohexyl-3-hydroxy-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(S)-6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid; and3-[(S)-6-Cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid; and the pharmaceutically acceptable salts thereof.
 11. A method ofreducing HCV viral load in a subject, wherein the method comprisesadministering to the subject a therapeutically effective amount of thecompound of Formula (I):

or a pharmaceutically acceptable salt thereof, wherein m is 0, 1 or 2; nis 0 or 1, wherein m+n is 1, 2 or 3; R₁ is C₃-C₁₀alkynyl or phenyl,which phenyl is substituted with 0, 1, 2, or 3 substituents which areindependently selected from the group consisting of halogen, hydroxy,cyano, C₁-C₄alkyl, haloC₁-C₄alkyl and C₁-C₄alkoxy, and which alkynyl isoptionally substituted with a C₃-C₇cycloalkyl substituent, whichcycloalkyl is optionally substituted with 1 or 2 independently selectedC₁-C₄alkyl groups; R₂ is CO₂H or C(O)N(H)S(O)₂CH₃; R₃ is C₃-C₇cycloalkylwhich is substituted with 0, 1, 2 or 3 halogen atoms; R_(3a) represents0, 1, 2, 3 or 4 residues independently selected at each occurrence fromthe group consisting of hydroxy, amino, cyano, halogen, C₁-C₆alkyl, andC₁-C₆alkoxy, wherein each alkyl or alkoxy substituent is substitutedwith 0, 1, or 2 substituents independently selected from hydroxy, cyano,C₁-C₄alkoxy, C₁-C₄alkylsulfone, N(R_(3b))₂, C(O)N(R_(3b)), heterocyclehaving 4 to 7 ring atoms and 1 or 2 ring heteroatoms selected from N, Oand S and 5 or 6 member heteroaryl; or two geminal R_(3a) substituents,taken in combination form a spirocyclic 3 to 6 member cycloalkyl orheterocycle; R_(3b) is independently selected at each occurrence fromhydrogen, C₁-C₄alkyl, C₁-C₄alkoxyC₁-C₄alkyl and C₁-C₄alkanoyl; orN(R_(3b))₂, taken in combination, form a 4 to 6 member heterocyclehaving 0 or 1 additional ring heteroatoms selected from N, O and S; X isO, N-L-R₄ or CR₅R₆; L is a bond, S(O)₂ or C(O); R₄ is C₁-C₆alkyl orC₃-C₇cycloalkyl each of which is substituted with 0, 1, or 2 hydroxy and0 or 1 substituents selected from cyano, S(O)₂—C₁-C₄alkyl, CO₂H orNR_(4a)R_(4b) or phenyl; R₄ is naphthyl or phenyl, which phenyl issubstituted with 0, 1, 2, or 3 substituents independently selected formthe group consisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl,C₁-C₆alkoxy, haloC₁-C₆alkoxy, amino, hydroxy, mono- anddi-C₁-C₆alkylamino, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₆alkyl-OC(O)NH—, C₁-C₄alkyl-C(O)NH—, —C(O)NR_(4a)R_(4b), phenyl,phenoxy, heteroaryl having one or two ring nitrogen atoms and having 0,1, or 2 C₁-C₄alkyl substituents, or two substituents combine to form afused heterocyclic ring, which heterocycle has 5, 6 or 7 ring atoms, 1or 2 ring heteroatoms selected from N, O and S and which heterocycle issubstituted with 0, 1 or 2 substituents independently selected fromC₁-C₆alkyl; or R₄ is a 5 or 6 member heteroaryl having 1 to 3heteroatoms selected from N, O and S, which heteroaryl is substitutedwith 0, 1, or 2 substituents independently selected from the groupconsisting of halogen, cyano, C₁-C₆alkyl, haloC₁-C₆alkyl, C₁-C₆alkoxy,haloC₁-C₆alkoxy, hydroxy, NR_(4a)R_(4b), hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₁-C₆alkyl-OC(O)NH—, C₃-C₇cycloalkyl,C₅-C₇cycloalkenyl, phenyl, 5 or 6 membered heteroaryl having 1 or 2 ringheteroatoms selected from N, O and S, and saturated or partiallyunsaturated monocyclic or bicyclic heterocycle which heterocycle has 1or 2 ring N, O or S atoms, 5 to 7 ring atoms in each ring and issubstituted with 0, 1 or 2 substituents independently selected from thegroup consisting of halogen, C₁-C₆alkyl, C₁-C₆alkanoyl,C₁-C₆alkoxyC(O)N(H)—, —C₁-C₆alkoxyC(O)N(H)CH₂—, aminoC₁-C₄alkyl,C₁-C₄alkoxyC₁-C₄alkyl and NR_(4a)R_(4b), and wherein the phenyl orheteroaryl substituent is unsubstituted or substituted with 1 or 2independently selected substituents selected from halogen, CO₂H, cyano,C₁-C₄alkyl, C₁-C₄alkoxy, CH₂NR_(4a)R_(4b) and C(O)NR_(4a)R_(4b); or R₄is a saturated heterocycle having 1 ring nitrogen and 0 or 1 additionalring heteroatom selected from N, O and S, which heterocyclic ring issubstituted with 0, 1, or 2 substituents independently selected from thegroup consisting of C₁-C₆alkyl, CO₂C₁-C₆alkyl and CO₂benzyl; R_(4a) isindependently selected at each occurrence from the group consisting ofhydrogen and C₁-C₆alkyl, wherein the alkyl substituent is unsubstitutedor substituted with hydroxy, C₁-C₄alkoxy, amino or mono- anddi-C₁-C₄alkylamino; R_(4b) is independently selected at each occurrencefrom the group consisting of hydrogen, C₁-C₆alkyl and C₁-C₄alkanoyl,wherein the alkyl substituent is unsubstituted or substituted withhydroxy, C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino; orNR_(4a)R_(4b), taken in combination, form a heterocyclic ring having onering nitrogen atom and 0 or 1 additional ring heteroatom selected fromN, O and S, which heterocyclic ring is substituted with 0, 1, 2 or 3substituents independently selected from the group consisting ofhalogen, hydroxy, amino, C₁-C₄alkyl, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl,aminoC₁-C₄alkyl, C₁-C₄alkoxy, C₁-C₄alkoxyC₁-C₄alkyl, and mono- anddi-C₁-C₄alkylamino; R₅ is absent or is selected from the groupconsisting of hydrogen and C₁-C₆alkyl; R₆ is oxo, hydrogen, hydroxy,amino, N(H)-J-R₇; J is absent, C(O) or S(O)₂; and R₇ is C₁-C₆alkyl,phenyl or benzyl, each of is optionally substituted with C₁-C₆alkyl,C₁-C₆alkoxy, halogen, phenyl or phenoxy.
 12. The method of claim 11,wherein the compound is a compound of formula II, or a pharmaceuticallyacceptable salt thereof:

wherein Z is CH or N; R₈ is selected from hydrogen, CO₂H, C₁-C₄alkyl,C-C₄alkoxy, cyano and halogen; R₉ is selected from C₁-C₆alkyl,C₁-C₆alkoxy, phenyl, NR_(9a)R_(9b), N(H)—C(O)—O—C₁-C₄alkyl, andheterocycle, wherein the heterocycle has one or two rings, each ringhaving 5, 6, or 7 ring atoms, one ring nitrogen atom and 0 or 1additional ring heteroatom selected from N, O and S, and wherein theheterocycle is unsubstituted or substituted with 1, 2 or 3 substituentsindependently selected from the group consisting of halogen, hydroxy,amino, C₁-C₄alkyl, haloC₁-C₄alkyl, hydroxyC₁-C₄alkyl, aminoC₁-C₄alkyl,C₁-C₄alkoxy, C₁-C₄alkoxyC₁-C₄alkyl, and mono- and di-C₁-C₄alkylaminoR_(9a) is selected from the group consisting of hydrogen and C₁-C₆alkyl,wherein the alkyl substituent is unsubstituted or substituted withhydroxy, C₁-C₄alkoxy, amino or mono- and di-C₁-C₄alkylamino; and R_(9b)is selected from the group consisting of hydrogen, C₁-C₆alkyl andC₁-C₄alkanoyl, wherein the alkyl substituent is unsubstituted orsubstituted with hydroxy, C₁-C₄alkoxy, amino or mono- anddi-C₁-C₄alkylamino.
 13. The method of claim 11, wherein the compound isa compound of formula III, or a pharmaceutically acceptable saltthereof:

wherein R₆ is hydrogen, hydroxy, amino or N(H)-J-R₇; J is C(O) or S(O)₂;R₇ is (a) C₁-C₄alkyl optionally substituted with phenyl or phenoxy, or(b) phenyl optionally substituted with C₁-C₄alkyl, halogen orC₁-C₄alkoxy; R₁₀ is selected from hydrogen and C₁-C₆alkyl which alkyl issubstituted with 0, 1, or 2 hydroxy and 0 or 1 substituents selectedfrom cyano, SO₂CH₃, methoxy, ethoxy, N(R_(10a))₂ and C(O)(NR_(10a))₂;R_(10a) is selected at each occurrence from the group consisting ofhydrogen and C₁-C₄alkyl which is substituted with 0 or 1 substituentsselected from hydroxy, methoxy and ethoxy; R₁₁ is selected from thegroup consisting of hydrogen, fluoro, cyano, hydroxy and C₁-C₄alkyl. 14.The method of claim 11, wherein the compound is a compound of formulaIV, or a pharmaceutically acceptable salt thereof:

wherein R₁₀ and R₁₁ are independently selected from hydrogen andC₁-C₆alkyl which alkyl is substituted with 0, 1, or 2 hydroxy and 0 or 1substituents selected from SO₂CH₃, cyano, methoxy, ethoxy, N(R_(10a))₂and C(O)N(R_(10a))₂; R_(10a) is selected at each occurrence from thegroup consisting of hydrogen and C₁-C₄alkyl which is substituted with 0or 1 substituents selected from hydroxy, methoxy and ethoxy, orN(R_(10a))₂, taken in combination forms a 4 to 6 member heterocyclicring; R₁₂ is selected from the group consisting of hydrogen andC₁-C₄alkyl.
 15. The method of claim 11, wherein R₁ is tert-butylethynyl,phenyl, or phenyl para-substituted with F, Cl, or Me.
 16. The method ofclaim 15, wherein R₁ is tert-butylethynyl.
 17. The method of claim 11,wherein R₂ is CO₂H.
 18. The method of claim 11, wherein R₃ iscyclohexyl.
 19. The method of claim 11, wherein the compound is selectedfrom the group consisting of:3-((S)-2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-phenyl-thiophene-2-carboxylicacid;3-(3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-(4-fluoro-phenyl)-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-6-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;5-(4-Chloro-phenyl)-3-(2-cyclohexyl-6-oxo-piperidin-1-yl)-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-4-(6-dipropylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((R)-2-methyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(6-pyrrolidin-1-yl-pyridine-3-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((2S,5R)-2,5-dimethyl-pyrrolidin-1-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-6-oxo-4-(toluene-4-sulfonyl)-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-((2R,6S)-2,6-dimethyl-morpholin-4-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-phenyl-thiophene-2-carboxylicacid;3-[2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-diethylamino-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-6-oxo-4-(3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-5′-sulfonyl)-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-((R)-4-Cyclohexyl-2-oxo-oxazolidin-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-morpholin-4-yl-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-phenyl-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(4-methoxy-benzenesulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(6-methoxy-pyridine-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-2-Cyclohexyl-4-(1-methyl-1H-pyrazole-3-sulfonyl)-6-oxo-piperazin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-2-Cyclohexyl-4-[6-(8-oxa-3-aza-bicyclo[3.2.1]oct-3-yl)-pyridine-3-sulfonyl]-6-oxo-piperazin-1-yl}-5-p-tolyl-thiophene-2-carboxylicacid;3-(2-Cyclohexyl-5-oxo-pyrrolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-3-Cyclohexyl-5-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((4S,5R)-5-Cyclohexyl-3,4-dimethyl-2-oxo-imidazolidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;5-(4-Chloro-phenyl)-3-((R)-3-cyclohexyl-5-oxo-morpholin-4-yl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(2-morpholin-4-yl-2-oxo-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(R)-5-Cyclohexyl-2-(3-methanesulfonyl-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-{(R)-5-Cyclohexyl-2-[(2-methoxy-ethylamino)-methyl]-3-oxo-morpholin-4-yl}-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(4-Cyclohexyl-2-oxo-[1,3]oxazinan-3-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2-morpholin-4-ylmethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((2S,5R)-2-Cyanomethyl-5-cyclohexyl-2-methyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2,2-dimethyl-3-oxo-morpholin-4-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-3-methyl-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((R)-3-hydroxy-butyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-(6-Cyclohexyl-3-hydroxy-3-methyl-2-oxo-piperidin-1-yl)-5-p-tolyl-thiophene-2-carboxylicacid;3-((R)-3-Cyclohexyl-5-oxo-1,9-dioxa-4-aza-spiro[5.5]undec-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((R)-5-Cyclohexyl-2-hydroxymethyl-3-oxo-morpholin-4-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[6-Cyclohexyl-3-hydroxy-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2,3-dihydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(2-hydroxy-ethyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-2-methyl-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-6-Cyclohexyl-3-hydroxy-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2S,5R)-5-Cyclohexyl-2-(3-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((R)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(2R,5R)-5-Cyclohexyl-2-((S)-2-hydroxy-propyl)-3-oxo-morpholin-4-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-[(S)-6-Cyclohexyl-3-(3-hydroxy-propyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid;3-((S)-3-Amino-6-cyclohexyl-2-oxo-piperidin-1-yl)-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid; and3-[(S)-6-Cyclohexyl-3-(2-hydroxy-ethyl)-2-oxo-piperidin-1-yl]-5-(3,3-dimethyl-but-1-ynyl)-thiophene-2-carboxylicacid; and the pharmaceutically acceptable salts thereof.